模拟微重力效应对海藻酸钠三维培养心肌细胞的影响
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摘要
微重力可致航天员在太空飞行过程中生理机能发生改变。这些变化主要包括心血管系统、肌肉系统、免疫系统和骨骼系统的病理性改变，其中心血管系统病理性改变是造成空间飞行过程中航天员不能顺利完成空间作业，甚至猝死的主要原因。因此，探讨微重力对心脏结构和功能的影响及其相关机制，可为进一步建立基于生物医学基础的有效防护措施提供理论基础，对于保证航天员在太空飞行时的健康和有效工作具有重要意义。
由于在空间进行微重力实验耗资大，机会有限，因此地面模拟微重力效应是目前空间生物学与航天医学研究的主要研究方式。为了克服模拟微重力效应研究中细胞二维培养的不足，本研究构建了一种新型的海藻酸钠微囊体，使细胞在该载体内呈三维生长，以保证尽可能实现在体细胞的特征。为了选择力学性能稳定，可以对抗回转过程产生的剪切力作用的载体材料，本实验首先利用流变仪检测了不同组成成分的海藻酸钠微囊体力学性能，结果显示1:30:0.05海藻酸钠/胶原/壳聚糖为最佳组成。扫描电镜显示微囊体为内部多孔结构，有利于细胞培养。其次，细胞增殖实验表明心肌细胞在该微囊体内的稳定增殖，原代心肌细胞在微囊体内可形成类心肌组织，并维持长期搏动。因此，海藻酸钠/胶原/壳聚糖微囊体包覆心肌细胞可用于后续微重力效应的相关研究。
为了进一步研究海藻酸钠微囊体用于模拟微重力效应研究的可靠性，本研究利用回转仪以转数15rpm回转培养24hr，比较海藻酸钠微囊体和cytodex微球为载体的心肌细胞微丝结构改变，发现两者微丝结构变化相似，此外不同表型的乳腺癌细胞在海藻酸钠微囊体中回转培养48hr后，乳腺癌细胞的生物学特性发生改变，表明海藻酸钠微囊体用于模拟微重力效应研究的可行性。
在构建以海藻酸钠微囊体为载体的细胞三维培养模型基础上，本文利用免疫荧光染色、MTT和流式细胞仪等方法研究了模拟微重力效应对心肌细胞结构、增殖和凋亡的影响，结果表明模拟微重力效应24hr导致三维培养的心肌细胞伪足消失，增殖能力降低，36hr出现早期凋亡，并在回转培养72hr时出现DNA损伤。
为了深入研究模拟微重力效应对三维培养的心肌细胞功能的影响及其相应机制，本研究还分析了心肌细胞搏动频率的变化，通过显微镜观察海藻酸钠微囊体内心肌细胞的搏动频率，发现模拟微重力效应24hr可致原代心肌细胞收缩频率改变，表明模拟微重力效应改变三维培养的心肌细胞的搏动功能。同时利用实时定量PCR和Western-blot分析了模拟微重力效应与介导兴奋-收缩耦联的缝隙连接蛋白Connexin43以及影响心肌功能的离子通道蛋白（钠离子通道蛋白、L-钙离子通道蛋白、钠钾泵、钠氢交换体）表达变化的关系，研究结果提示模拟微重力效应对编码钠通道的基因SCN5a表达未造成明显影响，而其余通道蛋白均有不同程度的表达变化（Connexin43表达呈一过性改变，可产生适应性恢复；L-钙通道蛋白表达增高；钠钾泵和钠氢交换体表达降低），说明模拟微重力效应改变了动作电位产生的分子基础，从而导致心肌搏动功能改变。此外，尾悬吊大鼠实验也表明模拟微重力效应改变了心肌离子通道蛋白表达，其中Connexin43和钠氢交换体改变与体外培养的心肌细胞改变一致，而L-钙通道蛋白和钠钾泵表达与体实验相反，以上研究结果提示神经体液调控参与了模拟微重力效应下心肌组织离子通道蛋白的表达。
在以上研究的基础上，为了深入分析模拟微重力效应下线粒体氧化应激响应的协同变化，利用线粒体特异探针荧光染色、活性氧探针DCFH-DA、Rh123染色以及抗氧化酶活性检测试剂盒研究了心肌细胞氧化应激的发生及相关机制，结果表明模拟微重力效应24hr心肌线粒体分布发生改变，48hr细胞活性氧显著增加，线粒体膜电位改变，导致心肌处于氧化应激状态。同时心肌细胞抗氧化物酶活性增强、热休克蛋白和转录因子NF-κB高表达。抗氧化物SOD活性分析表明回转培养的氧化应激机制可能以超氧化物为主。此外，线粒体的氧化应激研究结果也提示氧化应激参与了心肌细胞模拟微重力效应的响应机制，而且与心肌细胞搏动变化及部分离子通道的变化具有一致性。
综上，本研究通过构造新型海藻酸钠微囊体，建立了适用于模拟微重力效应研究的细胞三维培养体系，同时通过系统的探讨心肌细胞对空间微重力环境的响应及其功能变化，证实模拟微重力效应会导致心肌细胞骨架改变，并引起线粒体分布发生变化，活性氧显著增加，线粒体膜电位改变，使心肌处于氧化应激状态。同时引起缝隙连接蛋白和离子通道蛋白的表达改变，最终导致原代心肌细胞搏动功能紊乱。
Microgravity caused changes in physiological function of astronaut in spaceflight. These changes include the cardiovascular system, muscle system, the immunesystem and the skeletal system. Among them, the cardiovascular system change ispathological process, which caused the astronauts can't finish the homework space,and even the main cause of sudden death. Among those studies, the potential risksassociated with cardiovascular system have been a central concern in the study of thehuman physiologic adaptation to the microgravity environment. Therefore, toinvestigate the effects of microgravity on cardiac structure and function and itsmechanism is impotent, which to ensure the health and effective work of astronautsin space flight.
It is costly and limited opportunities for microgravity experiments in space;therefore, the ground simulation of microgravity effect is the main way of using. Inorder to reflection effect of simulated microgravity on myocardial cell in vivo, in thisstudy, three-dimensional myocardial cell is used to study effect of simulatedmicrogravity on myocardial cell structure and function. Using tissue engineeringbiotechnique, we provided the new carriers (alginate/collagen/chitosan hydrogel) toinvestigate the effect of simulated microgravity on biological characteristic ofcardiac cells. The results by a rheometer and SEM showed that the new carrierssystem was mechanically stable and porous scaffolds which allow cells to grow inthree-dimensional model. To evaluate whether the carriers are suitable to support thegrowth of mammalian cells, the viability of H9c2cells was assessed by MTT assayand the electrophysiologic characteristics of cardiac myocytes was investigate. Theresults showed that the viability of cells within carriers steadily increased, and thespontaneous and synchronous contraction of the whole cardiac cell-carriers wasmaintained more than two months.
In order to prove the alginate carriers encapsulated cell system for the reliabilityof the effect of simulated microgravity, it was observed the simulated microgravityeffect on H9c2microfilament cultured in alginate microcapsules and cytodexes, andthe biological characteristics of breast cancer cells cultured in simulated microgravity effect. The results showed that simulated microgravity effect usedNASA-RCCS with15rpm leaded to microfilament change in two carriers anddifferent biological alteration in two phenotypical dissimilar human breast cancercell lines, which was proved be suitable for alginate encapsulation of cells to studythe effect of simulated microgravity.
Furthermore, the effect of simulated microgravity with the establishedthree-dimensional cell culture model on structure, proliferation and apoptosis ofcardiomyocyte was analysed. The results showed that simulated microgravity effectused alginate carriers decreased cardiomyocytes proliferation, lead to cytoskeletondepolymerization, induced apoptosis in72hr. However, under2D rotation systemH9c2cells showd decreased cell area and cytoskeleton damage on day8, while noeffect was observed on cell proliferation;
Finally, effect of simulated microgravity on myocardial cells pulse functionwas observed. Simulated microgravity effect changed the frequency of myocardialcontractility. Furthermore, at the molecular level analysis of the impact of channelsprotein expression used transfer sodium, potassium and calcium ion, and signaltransduction of Cx43gap junction protein expression. Study found that cell modelsand animal models of simulated microgravity in the microgravity on the geneencoding sodium channel SCN5a expression did not cause significant impact, whilethe remaining changes the action potential of the structural basis, leading heart theoccurrence of disorders.
In this study, the mitochondrial specific probe Mito Tracker Red, reactiveoxygen species probe DCFH-DA, Rhodamine123, and antioxidant enzyme activityassay kits were used. The results revealed that3D rotation caused by simulatedmicrogravity effect mitochondrial distribution, structure and dysfunction, leaded tomyocardial oxidative stress in myocardial cells, increased antioxidant enzymeactivity and heat shock protein and transcription factor NF-κB expression.
In summary, this study established a three-dimensional carrier systerm foreffects of simulated microgravity. It indicated simulated microgravity at the cellularlevel changed myocardial structure and function, and impacted expression of ionchannels protein; and that simulated microgravity lead to the occurrence of oxidativestress. And in vivo experiments, simulated microgravity change the expression of iontchannel protein.
由于在空间进行微重力实验耗资大，机会有限，因此地面模拟微重力效应是目前空间生物学与航天医学研究的主要研究方式。为了克服模拟微重力效应研究中细胞二维培养的不足，本研究构建了一种新型的海藻酸钠微囊体，使细胞在该载体内呈三维生长，以保证尽可能实现在体细胞的特征。为了选择力学性能稳定，可以对抗回转过程产生的剪切力作用的载体材料，本实验首先利用流变仪检测了不同组成成分的海藻酸钠微囊体力学性能，结果显示1:30:0.05海藻酸钠/胶原/壳聚糖为最佳组成。扫描电镜显示微囊体为内部多孔结构，有利于细胞培养。其次，细胞增殖实验表明心肌细胞在该微囊体内的稳定增殖，原代心肌细胞在微囊体内可形成类心肌组织，并维持长期搏动。因此，海藻酸钠/胶原/壳聚糖微囊体包覆心肌细胞可用于后续微重力效应的相关研究。
为了进一步研究海藻酸钠微囊体用于模拟微重力效应研究的可靠性，本研究利用回转仪以转数15rpm回转培养24hr，比较海藻酸钠微囊体和cytodex微球为载体的心肌细胞微丝结构改变，发现两者微丝结构变化相似，此外不同表型的乳腺癌细胞在海藻酸钠微囊体中回转培养48hr后，乳腺癌细胞的生物学特性发生改变，表明海藻酸钠微囊体用于模拟微重力效应研究的可行性。
在构建以海藻酸钠微囊体为载体的细胞三维培养模型基础上，本文利用免疫荧光染色、MTT和流式细胞仪等方法研究了模拟微重力效应对心肌细胞结构、增殖和凋亡的影响，结果表明模拟微重力效应24hr导致三维培养的心肌细胞伪足消失，增殖能力降低，36hr出现早期凋亡，并在回转培养72hr时出现DNA损伤。
为了深入研究模拟微重力效应对三维培养的心肌细胞功能的影响及其相应机制，本研究还分析了心肌细胞搏动频率的变化，通过显微镜观察海藻酸钠微囊体内心肌细胞的搏动频率，发现模拟微重力效应24hr可致原代心肌细胞收缩频率改变，表明模拟微重力效应改变三维培养的心肌细胞的搏动功能。同时利用实时定量PCR和Western-blot分析了模拟微重力效应与介导兴奋-收缩耦联的缝隙连接蛋白Connexin43以及影响心肌功能的离子通道蛋白（钠离子通道蛋白、L-钙离子通道蛋白、钠钾泵、钠氢交换体）表达变化的关系，研究结果提示模拟微重力效应对编码钠通道的基因SCN5a表达未造成明显影响，而其余通道蛋白均有不同程度的表达变化（Connexin43表达呈一过性改变，可产生适应性恢复；L-钙通道蛋白表达增高；钠钾泵和钠氢交换体表达降低），说明模拟微重力效应改变了动作电位产生的分子基础，从而导致心肌搏动功能改变。此外，尾悬吊大鼠实验也表明模拟微重力效应改变了心肌离子通道蛋白表达，其中Connexin43和钠氢交换体改变与体外培养的心肌细胞改变一致，而L-钙通道蛋白和钠钾泵表达与体实验相反，以上研究结果提示神经体液调控参与了模拟微重力效应下心肌组织离子通道蛋白的表达。
在以上研究的基础上，为了深入分析模拟微重力效应下线粒体氧化应激响应的协同变化，利用线粒体特异探针荧光染色、活性氧探针DCFH-DA、Rh123染色以及抗氧化酶活性检测试剂盒研究了心肌细胞氧化应激的发生及相关机制，结果表明模拟微重力效应24hr心肌线粒体分布发生改变，48hr细胞活性氧显著增加，线粒体膜电位改变，导致心肌处于氧化应激状态。同时心肌细胞抗氧化物酶活性增强、热休克蛋白和转录因子NF-κB高表达。抗氧化物SOD活性分析表明回转培养的氧化应激机制可能以超氧化物为主。此外，线粒体的氧化应激研究结果也提示氧化应激参与了心肌细胞模拟微重力效应的响应机制，而且与心肌细胞搏动变化及部分离子通道的变化具有一致性。
综上，本研究通过构造新型海藻酸钠微囊体，建立了适用于模拟微重力效应研究的细胞三维培养体系，同时通过系统的探讨心肌细胞对空间微重力环境的响应及其功能变化，证实模拟微重力效应会导致心肌细胞骨架改变，并引起线粒体分布发生变化，活性氧显著增加，线粒体膜电位改变，使心肌处于氧化应激状态。同时引起缝隙连接蛋白和离子通道蛋白的表达改变，最终导致原代心肌细胞搏动功能紊乱。
Microgravity caused changes in physiological function of astronaut in spaceflight. These changes include the cardiovascular system, muscle system, the immunesystem and the skeletal system. Among them, the cardiovascular system change ispathological process, which caused the astronauts can't finish the homework space,and even the main cause of sudden death. Among those studies, the potential risksassociated with cardiovascular system have been a central concern in the study of thehuman physiologic adaptation to the microgravity environment. Therefore, toinvestigate the effects of microgravity on cardiac structure and function and itsmechanism is impotent, which to ensure the health and effective work of astronautsin space flight.
It is costly and limited opportunities for microgravity experiments in space;therefore, the ground simulation of microgravity effect is the main way of using. Inorder to reflection effect of simulated microgravity on myocardial cell in vivo, in thisstudy, three-dimensional myocardial cell is used to study effect of simulatedmicrogravity on myocardial cell structure and function. Using tissue engineeringbiotechnique, we provided the new carriers (alginate/collagen/chitosan hydrogel) toinvestigate the effect of simulated microgravity on biological characteristic ofcardiac cells. The results by a rheometer and SEM showed that the new carrierssystem was mechanically stable and porous scaffolds which allow cells to grow inthree-dimensional model. To evaluate whether the carriers are suitable to support thegrowth of mammalian cells, the viability of H9c2cells was assessed by MTT assayand the electrophysiologic characteristics of cardiac myocytes was investigate. Theresults showed that the viability of cells within carriers steadily increased, and thespontaneous and synchronous contraction of the whole cardiac cell-carriers wasmaintained more than two months.
In order to prove the alginate carriers encapsulated cell system for the reliabilityof the effect of simulated microgravity, it was observed the simulated microgravityeffect on H9c2microfilament cultured in alginate microcapsules and cytodexes, andthe biological characteristics of breast cancer cells cultured in simulated microgravity effect. The results showed that simulated microgravity effect usedNASA-RCCS with15rpm leaded to microfilament change in two carriers anddifferent biological alteration in two phenotypical dissimilar human breast cancercell lines, which was proved be suitable for alginate encapsulation of cells to studythe effect of simulated microgravity.
Furthermore, the effect of simulated microgravity with the establishedthree-dimensional cell culture model on structure, proliferation and apoptosis ofcardiomyocyte was analysed. The results showed that simulated microgravity effectused alginate carriers decreased cardiomyocytes proliferation, lead to cytoskeletondepolymerization, induced apoptosis in72hr. However, under2D rotation systemH9c2cells showd decreased cell area and cytoskeleton damage on day8, while noeffect was observed on cell proliferation;
Finally, effect of simulated microgravity on myocardial cells pulse functionwas observed. Simulated microgravity effect changed the frequency of myocardialcontractility. Furthermore, at the molecular level analysis of the impact of channelsprotein expression used transfer sodium, potassium and calcium ion, and signaltransduction of Cx43gap junction protein expression. Study found that cell modelsand animal models of simulated microgravity in the microgravity on the geneencoding sodium channel SCN5a expression did not cause significant impact, whilethe remaining changes the action potential of the structural basis, leading heart theoccurrence of disorders.
In this study, the mitochondrial specific probe Mito Tracker Red, reactiveoxygen species probe DCFH-DA, Rhodamine123, and antioxidant enzyme activityassay kits were used. The results revealed that3D rotation caused by simulatedmicrogravity effect mitochondrial distribution, structure and dysfunction, leaded tomyocardial oxidative stress in myocardial cells, increased antioxidant enzymeactivity and heat shock protein and transcription factor NF-κB expression.
In summary, this study established a three-dimensional carrier systerm foreffects of simulated microgravity. It indicated simulated microgravity at the cellularlevel changed myocardial structure and function, and impacted expression of ionchannels protein; and that simulated microgravity lead to the occurrence of oxidativestress. And in vivo experiments, simulated microgravity change the expression of iontchannel protein.
引文
[1] Wan L, Ogrinz B, Vigo D, Bersenev E, et al. Cardiovascular autonomicadaptation to long-term confinement during a105-day simulated Marsmission[J]. Aviat Space Environ Med,2011,82(7):711-6.
[2] Saxena R, Pan G, Dohm ED, McDonald JM. Modeled microgravity andhindlimb unloading sensitize osteoclast precursors to RANKL-mediatedsteoclastogenesis [J]. J Bone Miner Metab,2011,29(1):111-22.
[3] Pietsch J, Bauer J, Egli M, et al. The effects of weightlessness on the humanorganism and mammalian cells[J]. Curr Mol Med,2011,11(5):350-64.
[4] Meloni MA, Galleri G, Pani G, et al. Space flight affects motility andcytoskeletal structures in human monocyte cell line J-111[J]. Cytoskeleton(Hoboken),2011,68(2):125-37.
[5] Summers R, Coleman T, Steven P, et al. Systems analysis of the mechanisms ofcardiac diastolic function changes after microgravity exposure[J]. Acta Astr-onautica,2008,63(7-10):722-6.
[6] Sides MB, Vernikos J, Convertino VA, et al. The Bellagio Report:Cardiovascular risks of spaceflight: implications for the future of spacetravel[J]. Aviat Space Environ Med,2005,76(9):877-95.
[7] H s, B M, R T. Evidence based review: risk of cardiac rhythm problems duringspace flight[J]. National Technical Information Service,2010:1-17.
[8] Lyndon B. An Approach to Risk Reduction and Management for Human SpaceFlight[R]. Hoston,2004:1-92.
[9] Philpott DE, Popova IA, Kato K, Stevenson J, et al. Morphological andbiochemical examination of Cosmos1887rat heart tissue: Part–I Ultra-structure. Faseb J,1990,4(1):73-8.
[10] Goldstein MA, Edwards RJ, Schroeter JP. Cardiac morphology afterconditions of microgravity during COSMOS2044[J]. J Appl Physiol,1992,73(2Suppl):94S-100S.
[11] Thomason DB, Morrison PR, Oganov V, et al. Altered actin and myosinexpression in muscle during exposure to micro-gravity[J]. J Appl Physiol,1992,73(2Suppl):90S-3S.
[12] Keating MT, Sanguinetti MC. Molecular and cellular mechanisms of cardiacarrhythmias[J]. Cell,2001,104(4):569-80.
[13] Glitsch HG. Electrophysiology of the sodium-potassium-ATPase in cardiaccells[J]. Physiological Reviews,2001,81(4):1791-826.
[14] Swift F, Birkeland JA, Tovsrud N, et al. Altered Na+/Ca2+-exchanger activitydue to downregulation of Na+/K+-ATPase alpha2-isoform in heart failure[J].Cardiovasc Res,2008,78(1):71-8.
[15] Holthouser KA, Mandal A, Merchant ML, et al. Ouabain stimulates Na-K-ATPase through a sodium/hydrogen exchanger-1(NHE-1)-dependentmechanism in human kidney proximal tubule cells[J]. Am J Physiol RenalPhysiol,2010,299(1):F77-90.
[16] Amin AS, Tan HL, Wilde AA. Cardiac ion channels in health and disease[J].Heart Rhythm,2010,7(1):117-26.
[17] Amin AS, Asghari-Roodsari A, Tan HL. Cardiac sodium channelopathies[J].Pflugers Arch,2010,460(2):223-37.
[18] Shang LL, Sanyal S, Pfahnl AE, et al. NF-kappa B-dependent transcriptionalregulation of the cardiac scn5a sodium channel by angiotensin II[J].American Journal of Physiology-Cell Physiology,2008,294(1):C372-C9.
[19] Abriel H, Kass RS. Regulation of the voltage-gated cardiac sodium channelNav1.5by interacting proteins[J]. Trends Cardiovasc Med,2005,15(1):35-40.
[20] Roden DM, Balser JR, George AL, et al. Cardiac ion channels[J]. Annu RevPhysiol,2002,64:431-75.
[21] Urena J, Del Valle-Rodriguez A, Lopez-Barneo J. Metabotropic Ca2+channel-induced calcium release in vascular smooth muscle[J]. Cell Calcium,2007,42(4-5):513-20.
[22] Chen H, Liu LL, Ye LL, et al. Targeted inactivation of cystic fibrosistransmembrane conductance regulator chloride channel gene preventsischemic preconditioning in isolated mouse heart[J]. Circulation,2004,110(6):700-4.
[23] Duan D. Phenomics of cardiac chloride channels: the systematic study ofchloride channel function in the heart[J]. J Physiol,2009,587(Pt10):2163-77.
[24] Al-Khalili L, Kotova O, Tsuchida H, et al. ERK1/2mediates insulinstimulation of Na,K-ATPase by phosphorylation of the alpha-subunit inhuman skeletal muscle cells[J]. Journal of Biological Chemistry,2004,279(24):25211-8.
[25] Deschenes G, Gonin S, Zolty E, et al. Increased synthesis and AVPunresponsiveness of Na,K-ATPase in collecting duct from nephrotic rats[J].Journal of the American Society of Nephrology,2001,12(11):2241-52.
[26] Sweeney G, Klip A. Regulation of the Na+/K+-ATPase by insulin: Why andhow[J]? Molecular and Cellular Biochemistry,1998,182(1-2):121-33.
[27] Sweeney G, Somwar R, Ramlal T, et al. Insulin stimulation of K+uptake in3T3-L1fibroblasts involves phosphatidylinositol3-kinase and protein kinaseC-zeta. Diabetologia1998;41(10):1199-204.
[28] Fliegel L. The Na+/H+exchanger isoform1[J]. Int J Biochem Cell Biol,2005,37(1):33-7.
[29] Farwell D, Gollob MH. Electrical heart disease: Genetic and molecular basisof cardiac arrhythmias in normal structural hearts[J]. Can J Cardiol,2007,23Suppl A:16A-22A.
[30] Tribulova N, Knezl V, Okruhlicova L, et al. Myocardial gap junctions: targetsfor novel approaches in the prevention of life-threatening cardiacarrhythmias[J]. Physiol Res,2008,57Suppl2:S1-S13.
[31] Schimpf R, Veltmann C, Wolpert C, et al. Arrhythmogenic hereditarysyndromes: Brugada Syndrome, long QT syndrome, short QT syndrome andCPVT[J]. Minerva Cardioangiol,2010,58(6):623-36.
[32] Maeda S, Tsukihara T. Structure of the gap junction channel and itsimplications for its biological functions[J]. Cell Mol Life Sci,2011,68(7):1115-29.
[33] Herve JC, Derangeon M, Theveniau-Ruissy M, et al. Connexins andjunctional channels. Roles in the spreading of cardiac electrical excitation andheart development[J]. Pathol Biol (Paris),2008,56(5):334-41.
[34] Dimmeler S, Zeiher AM. A "reductionist" view of cardiomyopathy[J]. Cell,2007,130(3):401-2.
[35] Opara EC. Oxidative stress[J]. Dis Mon,2006,52(5):183-98.
[36] Shanati A, Rivlin Y, Shnizer S, et al. Serum oxidizability potential ofischemic heart disease patients is associated with exercise test results anddisease severity[J]. World J Cardiol,2009,1(1):46-50.
[37] Zucker IH, Schultz HD, Patel KP, et al. Regulation of central angiotensin type1receptors and sympathetic outflow in heart failure[J]. Am J Physiol HeartCirc Physiol,2009,297(5):H1557-66.
[38] Tisdale JE, Overholser BR, Sowinski KM, et al. Pharmacokinetics of ibutilidein patients with heart failure due to left ventricular systolic dysfunction[J].Pharmacotherapy,2008,28(12):1461-70.
[39] Tsutsui H, Ide T, Hayashidani S, et al. Greater susceptibility of failing cardiacmyocytes to oxygen free radical-mediated injury[J]. Cardiovasc Res,2001,49(1):103-9.
[40] Tsutsui H, Kinugawa S, Matsushima S. Mitochondrial oxidative stress anddysfunction in myocardial remodelling[J]. Cardiovasc Res,2009,81(3):449-56.
[41] Tsutsui H, Kinugawa S, Matsushima S, et al. Oxidative stress in cardiac andskeletal muscle dysfunction associated with diabetes mellitus[J]. J ClinBiochem Nutr,2011,48(1):68-71.
[42] Siwik DA, Tzortzis JD, Pimental DR, et al. Inhibition of copper-zincsuperoxide dismutase induces cell growth, hypertrophic phenotype, andapoptosis in neonatal rat cardiac myocytes in vitro[J]. Circ Res,1999,85(2):147-53.
[43] Hayashidani S, Tsutsui H, Ikeuchi M, et al. Targeted deletion of MMP-2attenuates early LV rupture and late remodeling after experimentalmyocardial infarction[J]. Am J Physiol Heart Circ Physiol,2003,285(3):H1229-35.
[44] Krishnamurthy P, Peterson JT, Subramanian V, et al. Inhibition of matrixmetalloproteinases improves left ventricular function in mice lackingosteopontin after myocardial infarction[J]. Mol Cell Biochem,2009,322(1-2):53-62.
[45] Kandalam V, Basu R, Abraham T, et al. Early activation of matrix metallopro-teinases underlies the exacerbated systolic and diastolic dysfunction in micelacking TIMP3following myocardial infarction[J]. Am J Physiol Heart CircPhysiol,2010,299(4):H1012-23.
[46] Yi ZC, Xia B, Xue M, et al. Simulated microgravity inhibits the proliferationof K562erythroleukemia cells but does not result in apoptosis[J]. Advancesin Space Research,2009,44(2):233-44.
[47] Huang Y, Dai ZQ, Ling SK, et al. Gravity, a regulation factor in thedifferentiation of rat bone marrow mesenchymal stem cells[J]. J Biomed Sci,2009,16:87.
[48] Takeda M, Magaki T, Okazaki T, et al. Effects of simulated microgravity onproliferation and chemosensitivity in malignant glioma cells[J]. Neurosci Lett,2009,463(1):54-9.
[49] Qian AR, Zhang W, Weng YY, et al. Gravitational environment produced by asuperconducting magnet affects osteoblast morphology and functions[J]. ActaAstronautica,2008,63(7-10):929-46.
[50] Clement JQ, Lacy SM, Wilson BL. Gene expression profiling of humanepidermal keratinocytes in simulated microgravity and recovery cultures[J].Genomics Proteomics Bioinformatics,2008,6(1):8-28.
[51] Chen J, Chen R, Gao S. Morphological characteristics and proliferation ofkeratocytes cultured under simulated microgravity[J]. Artif Organs,2007,31(9):722-31.
[52] Schatten H, Lewis ML, Chakrabarti A. Spaceflight and clinorotation causecytoskeleton and mitochondria changes and increases in apoptosis in culturedcells[J]. Acta Astronaut,2001,49(3-10):399-418.
[53] Sarkar D, Nagaya T, Koga K, et al. Culture in vector-averaged gravity underclinostat rotation results in apoptosis of osteoblastic ROS17/2.8cells[J]. JBone Miner Res,2000,15(3):489-98.
[54] Lewis ML, Reynolds JL, Cubano LA, et al. Spaceflight alters microtubulesand increases apoptosis in human lymphocytes (Jurkat)[J]. Faseb J,1998,12(11):1007-18.
[55] Grimm D, Bauer J, Kossmehl P, et al. Simulated microgravity altersdifferentiation and increases apoptosis in human follicular thyroid carcinomacells[J]. Faseb J,2002,16(6):604-6.
[56] Uva BM, Masini MA, Sturla M, et al. Microgravity-induced apoptosis incultured glial cells[J]. Eur J Histochem,2002,46(3):209-14.
[57] Grimm D, Kossmehl P, Shakibaei M, et al. Effects of simulated microgravityon thyroid carcinoma cells[J]. J Gravit Physiol,2002,9(1):P253-6.
[58] Boonyaratanakornkit JB, Cogoli A, Li CF, et al. Key gravity-sensitivesignaling pathways drive T cell activation[J]. Faseb J,2005,19(14):2020-2.
[59] Maccarrone M, Battista N, Meloni M, et al. Creating conditions similar tothose that occur during exposure of cells to microgravity induces apoptosis inhuman lymphocytes by5-lipoxygenase-mediated mitochondrial uncouplingand cytochrome c release[J]. J Leukoc Biol,2003,73(4):472-81.
[60] Cooper D, Pellis NR. Suppressed PHA activation of T lymphocytes insimulated microgravity is restored by direct activation of protein kinase C[J].J Leukoc Biol,1998,63(5):550-62.
[61] Schmitt DA, Hatton JP, Emond C, et al. The distribution of protein kinase Cin human leukocytes is altered in microgravity[J]. Faseb J,1996,10(14):1627-34.
[62] Hatton JP, Gaubert F, Cazenave JP, et al. Microgravity modifies proteinkinase C isoform translocation in the human monocytic cell line U937andhuman peripheral blood T-cells[J]. J Cell Biochem,2002,87(1):39-50.
[63] Kossmehl P, Shakibaei M, Cogoli A, et al. Simulated microgravity inducesprogrammed cell death in human thyroid carcinoma cells[J]. J Gravit Physiol,2002,9(1):P295-6.
[64] Nakamura H, Kumei Y, Morita S, et al. Antagonism between apoptotic(Bax/Bcl-2) and anti-apoptotic (IAP) signals in human osteoblastic cellsunder vector-averaged gravity condition[J]. Ann N Y Acad Sci,2003,1010:143-7.
[65] Loesberg WA, Walboomers XF, Van Loon JJ, et al. Simulated microgravityactivates MAPK pathways in fibroblasts cultured on microgrooved surfacetopography[J]. Cell Motil Cytoskeleton,2008,65(2):116-29.
[66] Grigoryan EN, Anton HJ, Mitashov VI. Microgravity effects on neural retinaregeneration in the newt[J]. Adv Space Res,1998,22(2):293-301.
[67] Grigoryan EN, Mitashov VI, Anton HJ. Urodelean amphibians in studies onmicrogravity: effects upon organ and tissue regeneration[J]. Adv Space Res,2002,30(4):757-64.
[68] Anton HJ, Koussoulakos S. Unilateral forelimb amputation affects proteinsynthesis in ipsilateral and contralateral spinal cord and spinal ganglianeurons of the newt in vivo[J]. Dev Neurosci,1993,15(2):121-7.
[69] Grigoryan EN, Anton HJ, Mitashov VI. Real and simulated microgravity canactivate signals stimulating cells to enter the S phase during lens regenerationin urodelean amphibians[J]. Advances in Space Research,2006,38(6):1071-8.
[70] Li S, Ma Z, Niu Z, et al. NASA-approved rotary bioreactor enhancesproliferation and osteogenesis of human periodontal ligament stem cells[J].Stem Cells Dev,2009,18(9):1273-82.
[71] Slentz DH, Truskey GA, Kraus WE. Effects of chronic exposure to simulatedmicrogravity on skeletal muscle cell proliferation and differentiation[J]. InVitro Cell Dev Biol Anim,2001,37(3):148-56.
[72] Unsworth BR, Lelkes PI. Growing tissues in microgravity[J]. Nat Med,1998,4(8):901-7.
[73] Plett PA, Frankovitz SM, Abonour R, et al. Proliferation of humanhematopoietic bone marrow cells in simulated microgravity[J]. In Vitro CellDev Biol Anim,2001,37(2):73-8.
[74] Chiu B, Wan JZ, Abley D, et al. Induction of vascular endothelial phenotypeand cellular proliferation from human cord blood stem cells cultured insimulated microgravity[J]. Acta Astronaut,2005,56(9-12):918-22.
[75] Li J, Zhang S, Chen J, et al. Modeled microgravity causes changes in thecytoskeleton and focal adhesions, and decreases in migration in malignanthuman MCF-7cells[J]. Protoplasma,2009,238(1-4):23-33.
[76]岳茗，张小铀，丁柏，等.模拟失重对培养心肌细胞形态和结构的影响[J].空间科学学报，1998，18(1):75-80.
[77]李莹辉，丁柏，汪恭质，等.药物对模拟失重条件下心肌细胞功能的保护作用[J].航天医学与医学工程，1999，17(5):326-8.
[78] Lecina M, Ting S, Choo A, et al. Scalable platform for human embryonicstem cell differentiation to cardiomyocytes in suspended microcarriercultures[J]. Tissue Eng Part C Methods,2011,16(6):1609-19.
[79] Shimada N, Sokunbi G, Moorman SJ. Changes in gravitational force affectgene expression in developing organ systems at different developmentaltimes[J]. BMC Dev Biol,2005,5:10.
[80] Morey-Holton ER, Globus RK. Hindlimb unloading rodent model: technicalaspects[J]. J Appl Physiol,2002,92(4):1367-77.
[81] Musacchia XJ, Fagette S. Weightlessness simulations for cardiovascular andmuscle systems: validity of rat models[J]. J Gravit Physiol,1997,4(3):49-59.
[82] Zhang LF. Vascular adaptation to microgravity: what have we learned[J]? JAppl Physiol,2001,91(6):2415-30.
[83] Zhang LF, Cheng JH, Liu X, et al. Cardiovascular changes of conscious ratsafter simulated microgravity with and without daily-Gx gravitation[J]. J ApplPhysiol,2008,105(4):1134-45.
[84] Powers J, Bernstein D. The mouse as a model of cardiovascular adaptations tomicrogravity[J]. J Appl Physiol,2004,97(5):1686-92.
[85] Somody L, Fagette S, Frutoso J, et al. Recording heart rate and blood pressurein rats during parabolic flight[J]. Life Sci,1998,63(10):851-7.
[86] Verheyden B, Liu J, Beckers F, et al. Adaptation of heart rate and bloodpressure to short and long duration space missions[J]. Respir PhysiolNeurobiol,2009,169Suppl1:S13-6.
[87] Grenon SM, Xiao X, Hurwitz S, et al. Simulated microgravity inducesmicrovolt T wave alternans[J]. Ann Noninvasive Electrocardiol,2005,10(3):363-70.
[88] Tank J, Baevsky RM, Funtova, II, et al. Orthostatic heart rate responses afterprolonged space flights[J]. Clin Auton Res,2011,21(2):121-4.
[89] JB C, MW B, w F. Cardiopulmonary function. In:Nicogossian A, Huntoon C,Pool S (eds): Spcace Physiology and Medicine,3rd Edition[J]. Philadelpha,Lea&Febiger1994:286-304.
[90] WR H, JF Z. Clinical aspects of crew health. In: Johnston R, Dietein LD,Berry CA (eds.): Biomedical Results of Apollo (NASA SP-368),SectionII,Chapter1[J]. Washington DC,1995.
[91] Douglas WR. Current status of space medicine and exobiology[J]. AviatSpace Environ Med,1978,49(7):902-4.
[92] R S, K S, D S, et al. Vectorcardiographic changes during extended spaceflight (M093): Observations at rest and during exercise. In: Johnson RS,Dietlein LF (eds): Biomedical Results of Skylab (NASA SP-377), Section V,Chapter33[C]. Washinton DC.1977.
[93] Bungo MW, Johnson PC, Jr. Cardiovascular examinations and observations ofdeconditioning during the space shuttle orbital flight test program[J]. AviatSpace Environ Med,1983,54(11):1001-4.
[94] Fritsch-Yelle JM, Leuenberger UA, D'Aunno DS. An episode of ventriculartachycardia during long-duration spaceflight[J]. Am J Cardiol,1998,81(11):1391-2.
[95] D'Aunno DS, Dougherty AH, DeBlock HF. Effect of short-and long-durationspaceflight on QTc intervals in healthy astronauts[J]. Am J Cardiol,2003,91(4):494-7.
[96] Rossum AC, Wood ML, Bishop SL, et al. Evaluation of cardiac rhythmdisturbances during extravehicular activity[J]. Am J Cardiol,1997,79(8):1153-5.
[97] Martin DS, South DA, Wood ML, et al. Comparison of echocardiographicchanges after short-and long-duration spaceflight[J]. Aviat Space EnvironMed,2002,73(6):532-6.
[98] Bungo MW, Goldwater DJ, Popp RL, et al. Echocardiographic evaluation ofspace shuttle crewmembers[J]. J Appl Physiol,1987,62(1):278-83.
[99] Schlagheck RA, Trach BL. Microgravity research results and experiencesfrom the NASA/MIR space station program[J]. Acta Astronautica,2003,53(12):983-96.
[100] Rummell JA, Sawin CF, Buderer MC, et al. Physiological response toexercise after space flight--Apollo14through Apollo17[J]. Aviat SpaceEnviron Med,1975,46(5):679-83.
[101] Smith RF, Stanton K, Stoop D, et al. Quantitative electrocardiography duringextended space flight[J]. Acta Astronaut,1975,2(1-2):89-102.
[102] Martin DS, South DA, Garcia KM, et al. Ultrasound in space[J]. UltrasoundMed Biol,2003,29(1):1-12.
[103] Dorfman TA, Levine BD, Tillery T, et al. Cardiac atrophy in womenfollowing bed rest[J]. J Appl Physiol,2007,103(1):8-16.
[104] Yu ZB, Bao JX, Ma J, et al. Changes in myocardial contractility andcontractile proteins after four weeks of simulated [correction of simulate]weightlessness in rats[J]. J Gravit Physiol,2000,7(2):P147-8.
[105] Tuday EC, Berkowitz DE. Microgravity and cardiac atrophy: no sexdiscrimination[J]. J Appl Physiol,2007,103(1):1-2.
[106] Riley DA, Thompson JL, Krippendorf BB. Review of spaceflight andhindlimb suspension unloading induced sarcomere damage and repair[J].Basic Appl Myol,1995,5(2):139-45.
[107] Rokhlenko KD, Mul'diiarov P. Myocardial ultrastructure of rats exposedaboard biosatellite "Cosmos-936"[J]. Kosm Biol Aviakosm Med,1981,15(1):77-82.
[108] Thomason DB, Anderson O, Menon V, et al. Fractal analysis of cytoskeletonrearrangement in cardiac muscle during head-down tilt[J]. J Appl Physiol,1996,81(4):1522-7.
[109] Connor MK, Hood DA. Effect of microgravity on the expression ofmitochondrial enzymes in rat cardiac and skeletal muscles[J]. J Appl Physiol,1998,84(2):593-8.
[110] Perhonen MA, Franco F, Lane LD, et al. Cardiac atrophy after bed rest andspaceflight[J]. J Appl Physiol,2001,91(2):645-53.
[111] Fen Y, Hui LY, Bai D, et al. Reduced function and disassembledmicrotubules of cultured cardiomyocytes in spaceflight[J]. Chinese ScienceBulletin,2008,53(8):1185-92.
[112] Yao YH, Xiong JH, Liang ZG, et al. Gray characteristic analysis ofmicrotubules in cardiac myocytes[J]. Space Med Med Eng (Beijing),2004,17(5):322-5.
[113] Kwon O, Tranter M, Jones WK, et al. Differential translocation of nuclearfactor-kappaB in a cardiac muscle cell line under gravitational changes[J]. JBiomech Eng,2009,131(6):064503.
[114] Hayden MS, Ghosh S. Signaling to NF-kappaB[J]. Genes Dev,2004,18(18):2195-224.
[115] Mercurio F, Manning AM. NF-kappaB as a primary regulator of the stressresponse[J]. Oncogene,1999,18(45):6163-71.
[116] Jones WK, Brown M, Wilhide M, et al. NF-kappaB in cardiovascular disease:diverse and specific effects of a "general" transcription factor[J]?Cardiovasc Toxicol,2005,5(2):183-202.
[117] Gordon JW, Shaw JA, Kirshenbaum LA. Multiple facets of NF-kappaB inthe heart: to be or not to NF-kappaB[J]. Circ Res,2011,108(9):1122-32.
[118] Guttridge DC, Mayo MW, Madrid LV, et al. NF-kappaB-induced loss ofMyoD messenger RNA: possible role in muscle decay and cachexia[J].Science,2000,289(5488):2363-6.
[119] Ladner KJ, Caligiuri MA, Guttridge DC. Tumor necrosis factor-regulatedbiphasic activation of NF-kappa B is required for cytokine-induced loss ofskeletal muscle gene products[J]. J Biol Chem,2003,278(4):2294-303.
[120] Hunter RB, Stevenson E, Koncarevic A, et al. Activation of an alternativeNF-kappaB pathway in skeletal muscle during disuse atrophy[J]. Faseb J,2002,16(6):529-38.
[121] Lawler JM, Song W, Demaree SR. Hindlimb unloading increases oxidativestress and disrupts antioxidant capacity in skeletal muscle[J]. Free RadicBiol Med,2003,35(1):9-16.
[122] Li YP, Chen Y, Li AS, et al. Hydrogen peroxide stimulatesubiquitinconjugating activity and expression of genes for specific E2and E3proteins in skeletal muscle myotubes[J]. Am J Physiol Cell Physiol,2003,285(4):C806-12.
[123] Liu Y, Shen T, Randall WR, et al. Signaling pathways in activity-dependentfiber type plasticity in adult skeletal muscle[J]. J Muscle Res Cell Motil,2005,26(1):13-21.
[124] Childs TE, Spangenburg EE, Vyas DR, et al. Temporal alterations in proteinsignaling cascades during recovery from muscle atrophy[J]. Am J PhysiolCell Physiol,2003,285(2):C391-8.
[125] Zhang P, Chen X, Fan M. Signaling mechanisms involved in disuse muscleatrophy[J]. Med Hypotheses,2007,69(2):310-21.
[126] Gustafsson T, Osterlund T, Flanagan JN, et al. Effects of3days unloadingon molecular regulators of muscle size in humans[J]. J Appl Physiol,2010,109(3):721-7.
[127] Dodd SL, Hain B, Senf SM, Judge AR. Hsp27inhibits IKKbeta-inducedNF-kappaB activity and skeletal muscle atrophy[J]. Faseb J,2009,23(10):3415-23.
[128] Petersen LG, Damgaard M, Petersen JC, et al. Mechanisms of increase incardiac output during acute weightlessness in humans[J]. J Appl Physiol,2011,111(2):407-11.
[129] Convertino VA, Polet JL, Engelke KA, et al. Evidence for increasedbeta-adrenoreceptor responsiveness induced by14days of simulatedmicrogravity in humans[J]. Am J Physiol,1997,273(1Pt2):R93-9.
[130] Martel E, Champeroux P, Lacolley P, et al. Central hypervolemia in theconscious rat: a model of cardiovascular deconditioning[J]. J Appl Physiol,1996,80(4):1390-6.
[131] Shellock FG, Swan HJ, Rubin SA. Early central venous pressure changes inthe rat during two different levels of head-down suspension[J]. Aviat SpaceEnviron Med,1985,56(8):791-5.
[132] Deavers DR, Musacchia XJ, Meininger GA. Model for antiorthostatichypokinesia: head-down tilt effects on water and salt excretion[J]. J ApplPhysiol,1980,49(4):576-82.
[133] Dunn CD, Johnson PC, Lange RD. Regulation of hematopoiesis in ratsexposed to antiorthostatic hypokinetic/hypodynamia: II. Mechanisms of the"anemia"[J]. Aviat Space Environ Med,1986,57(1):36-44.
[134] Gardner LB, Preston RA. University of Miami Division of ClinicalPharmacology Therapeutic Rounds: the water-intolerant patient andperioperative hyponatremia[J]. Am J Ther,2000,7(1):23-30.
[135] Desplanches D, Mayet MH, Sempore B, et al. Effect of spontaneousrecovery or retraining after hindlimb suspension on aerobic capacity[J]. JAppl Physiol,1987,63(5):1739-43.
[136] Overton JM, Woodman CR, Tipton CM. Effect of hindlimb suspension onVO2max and regional blood flow responses to exercise[J]. J Appl Physiol,1989,66(2):653-9.
[137] Woodman CR, Sebastian LA, Tipton CM. Influence of simulatedmicrogravity on cardiac output and blood flow distribution duringexercise[J]. J Appl Physiol,1995,79(5):1762-8.
[138] Yu ZB, Zhang LF, Jin JP. A proteolytic NH2-terminal truncation of cardiactroponin I that is up-regulated in simulated microgravity[J]. J Biol Chem,2001,276(19):15753-60.
[139] Convertino VA, Bloomfield SA, Greenleaf JE. An overview of the issues:physiological effects of bed rest and restricted physical activity[J]. Med SciSports Exerc,1997,29(2):187-90.
[140] Galvez AS, Diwan A, Odley AM, et al. Cardiomyocyte degeneration withcalpain deficiency reveals a critical role in protein homeostasis[J]. Circ Res,2007,100(7):1071-8.
[141] Razeghi P, Volpini KC, Wang ME, et al. Mechanical unloading of the heartactivates the calpain system[J]. J Mol Cell Cardiol,2007,42(2):449-52.
[142] Fagette S, Somody L, Bouzeghrane F, et al. Biochemical characteristics ofbeta-adrenoceptors in rats after an18-day spaceflight (LMS-STS78)[J].Aviat Space Environ Med,1999,70(10):1025-8.
[143] Li Y, Arnold JM, Pampillo M, et al. Taurine prevents cardiomyocyte deathby inhibiting NADPH oxidase-mediated calpain activation[J]. Free RadicBiol Med,2009,46(1):51-61.
[144] Chen M, He H, Zhan S, et al. Bid is cleaved by calpain to an activefragment in vitro and during myocardial ischemia/reperfusion[J]. J BiolChem,2001,276(33):30724-8.
[145] Li Y, Li Y, Feng Q, et al. Calpain activation contributes to hyperglycaemiainduced apoptosis in cardiomyocytes[J]. Cardiovasc Res,2009,84(1):100-10.
[146] Hikoso S, Ikeda Y, Yamaguchi O, et al. Progression of heart failure wassuppressed by inhibition of apoptosis signal-regulating kinase1viatranscoronary gene transfer[J]. J Am Coll Cardiol,2007,50(5):453-62.
[147] Gorza L, Menabo R, Di Lisa F, et al. Troponin T cross-linking in humanapoptotic cardiomyocytes[J]. Am J Pathol,1997,150(6):2087-97.
[148] Singh RB, Chohan PK, Dhalla NS, et al. The sarcoplasmic reticulumproteins are targets for calpain action in the ischemic-reperfused heart[J]. JMol Cell Cardiol2004;37(1):101-10.
[149] Bajaj G, Sharma RK. TNF-alpha-mediated cardiomyocyte apoptosis involvescaspase-12and calpain[J]. Biochem Biophys Res Commun,2006,345(4):1558-64.
[150] Chang H, Zhang L, Xu PT, et al. Nuclear translocation of calpain-2regulatespropensity toward apoptosis in cardiomyocytes of tail-suspended rats[J]. JCell Biochem,2011,112(2):571-80.
[151]熊江辉，李莹辉，聂捷琳.模拟微重力效应对心肌细胞一氧化氮水平的影响及其相关机制的研究[J].中国科学，2002，32(6):568-73.
[152] Moibenko OO, Sahach VF, Tkachenko MM, et al. Mechanisms of nitricoxide activity in cardiovascular system as a basis of pathogenetic therapy ofrelated diseases[J]. Fiziol Zh,2004,50(1):11-30.
[153] Dupont E, Cieniewski-Bernard C, Bastide B, et al. Electrostimulation duringhindlimb unloading modulates PI3K-AKT downstream targets withoutpreventing soleus atrophy and restores slow phenotype through ERK[J]. AmJ Physiol Regul Integr Comp Physiol,2011,300(2):R408-17.
[154] Siamwala JH, Majumder S, Tamilarasan KP, et al. Simulated microgravitypromotes nitric oxide-supported angiogenesis via the iNOS-cGMP-PKGpathway in macrovascular endothelial cells[J]. FEBS Lett,2010,584(15):3415-23.
[155]刘朝霞,李志力,汪德生,等.模拟失重对大鼠心肌组织缝隙连接蛋白表达谱的影响[J].航天医学与医学工程,2008,21(1):6-10.
[156] Xia Y, Gong KZ, Xu M, et al Regulation of gap-junction protein connexin43by beta-adrenergic receptor stimulation in rat cardiomyocytes[J]. ActaPharmacol Sin,2009,30(7):928-34.
[157] Merrill AH Jr., Wang E, Mullins RE, et al. Analyses of plasma for metabolicand hormonal changes in rats flown aboard COSMOS2044[J]. J ApplPhysiol,1992,73(2Suppl):132S-5S.
[158] Miu B, Martin TP, Roy RR, et al. Metabolic and morphologic properties ofsingle muscle fibers in the rat after spaceflight, Cosmos1887[J]. Faseb J,1990,4(1):64-72.
[159] Fareh J, Bayard B, Gabrion J, et al. Cardiac and plasma atrial natriureticpeptide after9-day hindlimb suspension in rats[J]. J Appl Physiol,1994,76(2):641-9.
[160] Menon V, Thomason DB. Head-down tilt increases rat cardiac muscle eIF-2alpha phosphorylation[J]. Am J Physiol,1995,269(3Pt1):C802-4.
[161] J C, LF Z, J M, et al. Ultrastructural changes of myocardium in long termtailsuspended rats[J]. Chin J Aviat Med,1995,6(3):133-7.
[162] C L, LF Z, QW M, et al. Changes of type Ⅰand type Ⅲcollagens in ratmyocardium after medium or long term simulated weightlessness[J]. Chin JAerospace Med,2000,11(1):39-42.
[163] Yang CB, Wang YC, Gao Y, Geng J, et al. Artificial gravity with ergometricexercise preserves the cardiac, but not cerebrovascular, functions during4days of head-down bed rest[J]. Cytokine,2011,56(3):648-55.
[164] Coupe M, Yuan M, Demiot C, et al. Low-magnitude whole body vibrationwith resistive exercise as a countermeasure against cardiovasculardeconditioning after60days of head-down bed rest[J]. Am J Physiol RegulIntegr Comp Physiol,2011,301(6):R1748-54.
[165] Wang YC, Yang CB, Wu YH, et al. Artificial gravity with ergometricexercise as a countermeasure against cardiovascular deconditioning during4days of head-down bed rest in humans[J]. Eur J Appl Physiol,2011,111(9):2315-25.
[166]宝珍，李勇枝，辛冰牧，等.药复方对尾吊大鼠心肌ATP酶、SDH和能荷值的影响[J].航天医学与医学工程，2004，17(5):326-8.
[167]张文辉，亓鹏，杨芬，等.地高辛对模拟失重后大鼠心室功能的影响[J].航天医学与医学工程，2008，21(2):93-6.
[168] Rose EA, Gelijns AC, Moskowitz AJ, et al. Long-term use of a leftventricular assist device for end-stage heart failure[J]. N Engl J Med,2001,345(20):1435-43.
[169] Elsdale T, Bard J. Collagen substrata for studies on cell behavior[J]. J CellBiol,1972,54(3):626-37.
[170] McGuigan AP, Bruzewicz DA, Glavan A, et al. Cell encapsulation insub-mm sized gel modules using replica molding[J]. PLoS One,2008,3(5):e2258.
[171] Hunt NC, Grover LM. Cell encapsulation using biopolymer gels forregenerative medicine[J]. Biotechnol Lett,2010,32(6):733-42.
[172] Karp JM, Yeh J, Eng G, et al. Controlling size, shape and homogeneity ofembryoid bodies using poly(ethylene glycol) microwells[J]. Lab Chip,2007,7(6):786-94.
[173] Soranzo C, Della Torre G, Ingrosso A. Formation, growth and morphology ofmulticellular tumor spheroids from a human colon carcinoma cell line(LoVo)[J]. Tumori,1986,72(5):459-67.
[174] Dhiman HK, Ray AR, Panda AK. Characterization and evaluation ofchitosan matrix for in vitro growth of MCF-7breast cancer cell lines[J].Biomaterials,2004,25(21):5147-54.
[175] Cukierman E, Pankov R, Yamada KM. Cell interactions withthree-dimensional matrices[J]. Curr Opin Cell Biol,2002,14(5):633-9.
[176] Cukierman E, Pankov R, Stevens DR, et al. Taking cell-matrix adhesions tothe third dimension[J]. Science,2001,294(5547):1708-12.
[177] Alsberg E, Kong HJ, Hirano Y, et al. Regulating bone formation viacontrolled scaffold degradation[J]. J Dent Res,2003,82(11):903-8.
[178] Wu YM, Tang J, Zhao P, et al. Morphological changes and molecularexpressions of hepatocellular carcinoma cells in three-dimensional culturemodel[J]. Exp Mol Pathol2009;87(2):133-40.
[179] Hunt NC, Grover LM. Cell encapsulation using biopolymer gels forregenerative medicine[J]. Biotechnol Lett,2010,32(6):733-42.
[180] Elliott NT, Yuan F. A review of three-dimensional in vitro tissue models fordrug discovery and transport studies[J]. J Pharm Sci,2010,100(1):59-74.
[181] Yamada KM, Cukierman E. Modeling tissue morphogenesis and cancer in3D[J]. Cell,2007,130(4):601-10.
[182] Engler AJ, Carag-Krieger C, Johnson CP, et al. Embryonic cardiomyocytesbeat best on a matrix with heart-like elasticity: scar-like rigidity inhibitsbeating[J]. J Cell Sci,2008,121(Pt22):3794-802.
[183] Discher DE, Mooney DJ, Zandstra PW. Growth factors, matrices, and forcescombine and control stem cells[J]. Science,2009,324(5935):1673-7.
[184] Mitragotri S, Lahann J. Physical approaches to biomaterial design[J]. NatMater,2009,8(1):15-23.
[185] Griffith LG, Swartz MA. Capturing complex3D tissue physiology in vitro[J].Nat Rev Mol Cell Biol,2006,7(3):211-24.
[186] Braccini A, Wendt D, Jaquiery C, et al. Three-dimensional perfusion cultureof human bone marrow cells and generation of osteoinductive grafts[J].Stem Cells,2005,23(8):1066-72.
[187] Guthke R, Zeilinger K, Sickinger S, et al. Dynamics of amino acidmetabolism of primary human liver cells in3D bioreactors[J]. BioprocessBiosyst Eng,2006,28(5):331-40.
[188] Pomahac B, Svensjo T, Yao F, et al. Tissue engineering of skin[J]. Crit RevOral Biol Med,1998,9(3):333-44.
[189] Bartholoma P, Gorjup E, Monz D, et al. Three-dimensional in vitroreaggregates of embryonic cardiomyocytes: a potential model system formonitoring effects of bioactive agents[J]. J Biomol Screen,2005,10(8):814-22.
[190] Borg TK, Baudino TA. Dynamic interactions between the cellularcomponents of the heart and the extracellular matrix[J]. Pflugers Arch,2011,462(1):69-74.
[191] Bursac N, Papadaki M, Cohen RJ, et al. Cardiac muscle tissue engineering:toward an in vitro model for electrophysiological studies[J]. Am J Physiol1999;277(2Pt2):H433-44.
[192]司徒镇强.细胞培养.世界图书出版公司[M].2007:107-8.
[194] Kofidis T, Akhyari P, Boublik J, et al. In vitro engineering of heart muscle:artificial myocardial tissue[J]. J Thorac Cardiovasc Surg2002;124(1):63-9.
[193] Wakabayashi S, Pang T, Su X, et al. A novel topology model of the humanNa(+)/H(+) exchanger isoform1[J]. J Biol Chem2000;275(11):7942-9.
[194] Bucaro MA, Zahm AM, Risbud MV, et al. The effect of simulatedmicrogravity on osteoblasts is independent of the induction of apoptosis[J].J Cell Biochem,2007,102(2):483-95.
[195] Vassy J, Portet S, Beil M, et al. Weightlessness acts on human breast cancercell line MCF-7[J]. Space Life Sciences: Gravitational Biology,2003,32(8):1595-603.
[196] Qian AR, Zhang W, Xie L, et al. Simulated weightlessness alters biologicalcharacteristics of human breast cancer cell line MCF-7[J]. Acta Astronautica,2008,63(7-10):947-58.
[197] Swayne TC, Boldogh IR, Pon LA. Imaging of the cytoskeleton andmitochondria in fixed budding yeast cells[J]. Methods Mol Biol,2009,586:171-84.
[198] Hong-xia Z, Wei-ming T, Lei Y, et al. Effect of simulated weightlessness onspindle apparatus structure and cell cycle of NIH3T3fibroblasts[J]. SpaceMedicine&Medical Engineering,2010,23(6):416-8.
[199] Zimmermann WH, Eschenhagen T. Embryonic stem cells for cardiac muscleengineering[J]. Trends Cardiovasc Med,2007,17(4):134-40.
[200] Ott HC, Davis BH, Taylor DA. Cell therapy for heart failure--muscle, bonemarrow, blood, and cardiac-derived stem cells[J]. Semin Thorac CardiovascSurg,2005,17(4):348-60.
[201] Lazerges M. Selective hypergravity stimulation: its effects on the humanbalance and gait functions. A model to assess, in normal gravity conditions,some aspects of the perturbations induced on human body by microgravityconditions[J]. Acta Astronaut,1990,22:375-80.
[202] Sumanasekera WK, Zhao L, Ivanova M, et al. Effect of estradiol anddihydrotestosterone on hypergravity-induced MAPK signaling and occludinexpression in human umbilical vein endothelial cells[J]. Cell Tissue Res,2006,324(2):243-53.
[203] Masini MA, Prato P, Scarabelli L, et al. In vitro effects of simulatedmicrogravity on Sertoli cell function[J]. Advances in Space Research,2011,47(4):575-81.
[204] Bucaro MA, Fertala J, Adams CS, et al. Bone cell survival in microgravity:evidence that modeled microgravity increases osteoblast sensitivity toapoptogens[J]. Ann N Y Acad Sci,2004,1027:64-73.
[205] Infanger M, Kossmehl P, Shakibaei M, et al. Simulated weightlessnesschanges the cytoskeleton and extracellular matrix proteins in papillarythyroid carcinoma cells[J]. Cell Tissue Res,2006,324(2):267-77.
[206] Kumei Y, Morita S, Katano H, et al. Microgravity signal ensnarls celladhesion, cytoskeleton, and matrix proteins of rat osteoblasts: osteopontin,CD44, osteonectin, and alpha-tubulin[J]. Ann N Y Acad Sci,2006,1090:311-7.
[207] klaus Legner. humans in space and space biology[C]. Austria,2011,77-13
[208]杨芬，李莹辉，丁柏.空间飞行条件下心肌细胞发生功能减退与微管解聚[J].科学通报，2008，53(5):561-7.
[209] Akins RE, Schroedl NA, Gonda SR, et al. Neonatal rat heart cells cultured insimulated microgravity[J]. In Vitro Cell Dev Biol Anim,1997,33(5):337-43.
[210] White RJ, Blomqvist CG. Central venous pressure and cardiac functionduring spaceflight[J]. J Appl Physiol,1998,85(2):738-46.
[211] Ray CA, Vasques M, Miller TA, et al. Effect of short-term microgravity andlong-term hindlimb unloading on rat cardiac mass and function[J]. J ApplPhysiol,2001,91(3):1207-13.
[212] Kanno S, Saffitz JE. The role of myocardial gap junctions in electricalconduction and arrhythmogenesis[J]. Cardiovasc Pathol,2001,10(4):169-77.
[213] Boengler K. Stimulation of cardiac beta-adrenoceptors targets connexin43[J]. Br J Pharmacol,2009,158(1):195-7.
[214] Kjenseth A, Fykerud T, Rivedal E, et al. Regulation of gap junctionintercellular communication by the ubiquitin system[J]. Cell Signal,2010,22(9):1267-73.
[215] Mehta PK, Griendling KK. Angiotensin II cell signaling: physiological andpathological effects in the cardiovascular system[J]. Am J Physiol CellPhysiol,2007,292(1):C82-97.
[216] Xue JH, Wang XC, Gao F, et al. Short-term simulated weightlessnessenhances response of L-type calcium channel to angiotensin II in cerebralvascular smooth muscle cells in rats[J]. Sheng Li Xue Bao,2011,63(1):81-8.
[217] Glitsch HG. Electrophysiology of the sodium-potassium-ATPase in cardiaccells. Physiol Rev,2001,81(4):1791-826.
[218] Tyapkina O, Volkov E, Nurullin L, et al. Resting membrane potential andNa+,K+-ATPase of rat fast and slow muscles during modeling ofhypogravity[J]. Physiol Res,2009,58(4):599-603.
[219] Swift F, Tovsrud N, Enger UH, et al. The Na+/K+-ATPase alpha2-isoformregulates cardiac contractility in rat cardiomyocytes[J]. Cardiovasc Res,2007,75(1):109-17.
[220] Al-Khalili L, Kotova O, Tsuchida H, et al. ERK1/2mediates insulin stimulation ofNa(+),K(+)-ATPase by phosphorylation of the alpha-subunit in human skeletal musclecells[J]. J Biol Chem,2004,279(24):25211-8.
[221] Wakabayashi S, Pang T, Su X, et al. Second mutations rescue point mutantof the Na(+)/H(+) exchanger NHE1showing defective surface expression[J].FEBS Lett,2000,487(2):257-61.
[222] Xue JH, Zhang LF, Ma J, Xie MJ. Differential regulation of L-type Ca2+channels in cerebral and mesenteric arteries after simulated microgravity inrats and its intervention by standing[J]. Am J Physiol Heart Circ Physiol,2007,293(1):H691-701.
[223] Shenkman BS, Nemirovskaya TL. Calcium-dependent signaling mechanismsand soleus fiber remodeling under gravitational unloading[J]. J Muscle ResCell Motil,2008,29(6-8):221-30.
[224] Nattel S, Li D. Ionic remodeling in the heart: pathophysiologicalsignificance and new therapeutic opportunities for atrial fibrillation[J]. CircRes,2000,87(6):440-7.
[225] Iwasaki YK, Yamashita T, Sekiguchi A, et al. A method for the simultaneousanalysis of mRNA levels of multiple cardiac ion channels with a multi-probeRNase protection assay[J]. Europace,2006,8(11):1011-5.
[226] Tsutsui H. Mitochondrial oxidative stress and heart failure[J]. Intern Med,2006,45(13):809-13.
[227] Majumder S, Siamwala JH, Srinivasan S, et al. Simulated microgravitypromoted differentiation of bipotential murine oval liver stem cells bymodulating BMP4/Notch1signaling[J]. J Cell Biochem,2011,112(7):1898-908.
[228] Li GB, Liu YD, Wang GH, et al. Reactive oxygen species and antioxidantenzymes activity of Anabaena sp. PCC7120(Cyanobacterium) undersimulated microgravity[J]. Acta Astronaut,2004,55(11):953-7.
[229] Wang J, Zhang J, Bai S, et al. Simulated microgravity promotes cellularsenescence via oxidant stress in rat PC12cells[J]. Neurochem Int,2009,55(7):710-6.
[230] Coletta DK, Mandarino LJ. Mitochondrial dysfunction and insulin resistancefrom the outside in: extracellular matrix, the cytoskeleton, andmitochondria[J]. Am J Physiol Endocrinol Metab,2011,301(5):E749-55.
[231] Belch JJ, Bridges AB, Scott N, et al. Oxygen free radicals and congestiveheart failure[J]. Br Heart J,1991,65(5):245-8.
[232] Hill MF, Singal PK. Antioxidant and oxidative stress changes during heartfailure subsequent to myocardial infarction in rats[J]. Am J Pathol,1996,148(1):291-300.
[233] Borchi E, Bargelli V, Stillitano F, et al. Enhanced ROS production byNADPH oxidase is correlated to changes in antioxidant enzyme activity inhuman heart failure[J]. Biochim Biophys Acta,2010,1802(3):331-8.
[234] Josephson RA, Silverman HS, Lakatta EG, et al. Study of the mechanisms ofhydrogen peroxide and hydroxyl free radical-induced cellular injury andcalcium overload in cardiac myocytes[J]. J Biol Chem,1991,266(4):2354-61.
[235] Ou Y, Liao GY, Wu WT. Potential use of hirudin in diabetic cataract: a studyof galactose mediated human lens epithelial cells injury[J]. Chem BiolInteract,2008,173(2):141-7.
[236] Iadecola C, Alexander M. Cerebral ischemia and inflammation[J]. Curr OpinNeurol,2001,14(1):89-94.
[237] Mattson MP. Neuronal life-and-death signaling, apoptosis, andneurodegenera-tive disorders[J]. Antioxid Redox Signal,2006,8(11-12):1997-2006.
[238] Mayer MP, Bukau B. Hsp70chaperones: cellular functions and molecularmechanism[J]. Cell Mol Life Sci,2005,62(6):670-84.
[239] Kalmar B, Greensmith L. Induction of heat shock proteins for protectionagainst oxidative stress[J]. Advanced Drug Delivery Reviews,2009,61(4):310-8.
[2] Saxena R, Pan G, Dohm ED, McDonald JM. Modeled microgravity andhindlimb unloading sensitize osteoclast precursors to RANKL-mediatedsteoclastogenesis [J]. J Bone Miner Metab,2011,29(1):111-22.
[3] Pietsch J, Bauer J, Egli M, et al. The effects of weightlessness on the humanorganism and mammalian cells[J]. Curr Mol Med,2011,11(5):350-64.
[4] Meloni MA, Galleri G, Pani G, et al. Space flight affects motility andcytoskeletal structures in human monocyte cell line J-111[J]. Cytoskeleton(Hoboken),2011,68(2):125-37.
[5] Summers R, Coleman T, Steven P, et al. Systems analysis of the mechanisms ofcardiac diastolic function changes after microgravity exposure[J]. Acta Astr-onautica,2008,63(7-10):722-6.
[6] Sides MB, Vernikos J, Convertino VA, et al. The Bellagio Report:Cardiovascular risks of spaceflight: implications for the future of spacetravel[J]. Aviat Space Environ Med,2005,76(9):877-95.
[7] H s, B M, R T. Evidence based review: risk of cardiac rhythm problems duringspace flight[J]. National Technical Information Service,2010:1-17.
[8] Lyndon B. An Approach to Risk Reduction and Management for Human SpaceFlight[R]. Hoston,2004:1-92.
[9] Philpott DE, Popova IA, Kato K, Stevenson J, et al. Morphological andbiochemical examination of Cosmos1887rat heart tissue: Part–I Ultra-structure. Faseb J,1990,4(1):73-8.
[10] Goldstein MA, Edwards RJ, Schroeter JP. Cardiac morphology afterconditions of microgravity during COSMOS2044[J]. J Appl Physiol,1992,73(2Suppl):94S-100S.
[11] Thomason DB, Morrison PR, Oganov V, et al. Altered actin and myosinexpression in muscle during exposure to micro-gravity[J]. J Appl Physiol,1992,73(2Suppl):90S-3S.
[12] Keating MT, Sanguinetti MC. Molecular and cellular mechanisms of cardiacarrhythmias[J]. Cell,2001,104(4):569-80.
[13] Glitsch HG. Electrophysiology of the sodium-potassium-ATPase in cardiaccells[J]. Physiological Reviews,2001,81(4):1791-826.
[14] Swift F, Birkeland JA, Tovsrud N, et al. Altered Na+/Ca2+-exchanger activitydue to downregulation of Na+/K+-ATPase alpha2-isoform in heart failure[J].Cardiovasc Res,2008,78(1):71-8.
[15] Holthouser KA, Mandal A, Merchant ML, et al. Ouabain stimulates Na-K-ATPase through a sodium/hydrogen exchanger-1(NHE-1)-dependentmechanism in human kidney proximal tubule cells[J]. Am J Physiol RenalPhysiol,2010,299(1):F77-90.
[16] Amin AS, Tan HL, Wilde AA. Cardiac ion channels in health and disease[J].Heart Rhythm,2010,7(1):117-26.
[17] Amin AS, Asghari-Roodsari A, Tan HL. Cardiac sodium channelopathies[J].Pflugers Arch,2010,460(2):223-37.
[18] Shang LL, Sanyal S, Pfahnl AE, et al. NF-kappa B-dependent transcriptionalregulation of the cardiac scn5a sodium channel by angiotensin II[J].American Journal of Physiology-Cell Physiology,2008,294(1):C372-C9.
[19] Abriel H, Kass RS. Regulation of the voltage-gated cardiac sodium channelNav1.5by interacting proteins[J]. Trends Cardiovasc Med,2005,15(1):35-40.
[20] Roden DM, Balser JR, George AL, et al. Cardiac ion channels[J]. Annu RevPhysiol,2002,64:431-75.
[21] Urena J, Del Valle-Rodriguez A, Lopez-Barneo J. Metabotropic Ca2+channel-induced calcium release in vascular smooth muscle[J]. Cell Calcium,2007,42(4-5):513-20.
[22] Chen H, Liu LL, Ye LL, et al. Targeted inactivation of cystic fibrosistransmembrane conductance regulator chloride channel gene preventsischemic preconditioning in isolated mouse heart[J]. Circulation,2004,110(6):700-4.
[23] Duan D. Phenomics of cardiac chloride channels: the systematic study ofchloride channel function in the heart[J]. J Physiol,2009,587(Pt10):2163-77.
[24] Al-Khalili L, Kotova O, Tsuchida H, et al. ERK1/2mediates insulinstimulation of Na,K-ATPase by phosphorylation of the alpha-subunit inhuman skeletal muscle cells[J]. Journal of Biological Chemistry,2004,279(24):25211-8.
[25] Deschenes G, Gonin S, Zolty E, et al. Increased synthesis and AVPunresponsiveness of Na,K-ATPase in collecting duct from nephrotic rats[J].Journal of the American Society of Nephrology,2001,12(11):2241-52.
[26] Sweeney G, Klip A. Regulation of the Na+/K+-ATPase by insulin: Why andhow[J]? Molecular and Cellular Biochemistry,1998,182(1-2):121-33.
[27] Sweeney G, Somwar R, Ramlal T, et al. Insulin stimulation of K+uptake in3T3-L1fibroblasts involves phosphatidylinositol3-kinase and protein kinaseC-zeta. Diabetologia1998;41(10):1199-204.
[28] Fliegel L. The Na+/H+exchanger isoform1[J]. Int J Biochem Cell Biol,2005,37(1):33-7.
[29] Farwell D, Gollob MH. Electrical heart disease: Genetic and molecular basisof cardiac arrhythmias in normal structural hearts[J]. Can J Cardiol,2007,23Suppl A:16A-22A.
[30] Tribulova N, Knezl V, Okruhlicova L, et al. Myocardial gap junctions: targetsfor novel approaches in the prevention of life-threatening cardiacarrhythmias[J]. Physiol Res,2008,57Suppl2:S1-S13.
[31] Schimpf R, Veltmann C, Wolpert C, et al. Arrhythmogenic hereditarysyndromes: Brugada Syndrome, long QT syndrome, short QT syndrome andCPVT[J]. Minerva Cardioangiol,2010,58(6):623-36.
[32] Maeda S, Tsukihara T. Structure of the gap junction channel and itsimplications for its biological functions[J]. Cell Mol Life Sci,2011,68(7):1115-29.
[33] Herve JC, Derangeon M, Theveniau-Ruissy M, et al. Connexins andjunctional channels. Roles in the spreading of cardiac electrical excitation andheart development[J]. Pathol Biol (Paris),2008,56(5):334-41.
[34] Dimmeler S, Zeiher AM. A "reductionist" view of cardiomyopathy[J]. Cell,2007,130(3):401-2.
[35] Opara EC. Oxidative stress[J]. Dis Mon,2006,52(5):183-98.
[36] Shanati A, Rivlin Y, Shnizer S, et al. Serum oxidizability potential ofischemic heart disease patients is associated with exercise test results anddisease severity[J]. World J Cardiol,2009,1(1):46-50.
[37] Zucker IH, Schultz HD, Patel KP, et al. Regulation of central angiotensin type1receptors and sympathetic outflow in heart failure[J]. Am J Physiol HeartCirc Physiol,2009,297(5):H1557-66.
[38] Tisdale JE, Overholser BR, Sowinski KM, et al. Pharmacokinetics of ibutilidein patients with heart failure due to left ventricular systolic dysfunction[J].Pharmacotherapy,2008,28(12):1461-70.
[39] Tsutsui H, Ide T, Hayashidani S, et al. Greater susceptibility of failing cardiacmyocytes to oxygen free radical-mediated injury[J]. Cardiovasc Res,2001,49(1):103-9.
[40] Tsutsui H, Kinugawa S, Matsushima S. Mitochondrial oxidative stress anddysfunction in myocardial remodelling[J]. Cardiovasc Res,2009,81(3):449-56.
[41] Tsutsui H, Kinugawa S, Matsushima S, et al. Oxidative stress in cardiac andskeletal muscle dysfunction associated with diabetes mellitus[J]. J ClinBiochem Nutr,2011,48(1):68-71.
[42] Siwik DA, Tzortzis JD, Pimental DR, et al. Inhibition of copper-zincsuperoxide dismutase induces cell growth, hypertrophic phenotype, andapoptosis in neonatal rat cardiac myocytes in vitro[J]. Circ Res,1999,85(2):147-53.
[43] Hayashidani S, Tsutsui H, Ikeuchi M, et al. Targeted deletion of MMP-2attenuates early LV rupture and late remodeling after experimentalmyocardial infarction[J]. Am J Physiol Heart Circ Physiol,2003,285(3):H1229-35.
[44] Krishnamurthy P, Peterson JT, Subramanian V, et al. Inhibition of matrixmetalloproteinases improves left ventricular function in mice lackingosteopontin after myocardial infarction[J]. Mol Cell Biochem,2009,322(1-2):53-62.
[45] Kandalam V, Basu R, Abraham T, et al. Early activation of matrix metallopro-teinases underlies the exacerbated systolic and diastolic dysfunction in micelacking TIMP3following myocardial infarction[J]. Am J Physiol Heart CircPhysiol,2010,299(4):H1012-23.
[46] Yi ZC, Xia B, Xue M, et al. Simulated microgravity inhibits the proliferationof K562erythroleukemia cells but does not result in apoptosis[J]. Advancesin Space Research,2009,44(2):233-44.
[47] Huang Y, Dai ZQ, Ling SK, et al. Gravity, a regulation factor in thedifferentiation of rat bone marrow mesenchymal stem cells[J]. J Biomed Sci,2009,16:87.
[48] Takeda M, Magaki T, Okazaki T, et al. Effects of simulated microgravity onproliferation and chemosensitivity in malignant glioma cells[J]. Neurosci Lett,2009,463(1):54-9.
[49] Qian AR, Zhang W, Weng YY, et al. Gravitational environment produced by asuperconducting magnet affects osteoblast morphology and functions[J]. ActaAstronautica,2008,63(7-10):929-46.
[50] Clement JQ, Lacy SM, Wilson BL. Gene expression profiling of humanepidermal keratinocytes in simulated microgravity and recovery cultures[J].Genomics Proteomics Bioinformatics,2008,6(1):8-28.
[51] Chen J, Chen R, Gao S. Morphological characteristics and proliferation ofkeratocytes cultured under simulated microgravity[J]. Artif Organs,2007,31(9):722-31.
[52] Schatten H, Lewis ML, Chakrabarti A. Spaceflight and clinorotation causecytoskeleton and mitochondria changes and increases in apoptosis in culturedcells[J]. Acta Astronaut,2001,49(3-10):399-418.
[53] Sarkar D, Nagaya T, Koga K, et al. Culture in vector-averaged gravity underclinostat rotation results in apoptosis of osteoblastic ROS17/2.8cells[J]. JBone Miner Res,2000,15(3):489-98.
[54] Lewis ML, Reynolds JL, Cubano LA, et al. Spaceflight alters microtubulesand increases apoptosis in human lymphocytes (Jurkat)[J]. Faseb J,1998,12(11):1007-18.
[55] Grimm D, Bauer J, Kossmehl P, et al. Simulated microgravity altersdifferentiation and increases apoptosis in human follicular thyroid carcinomacells[J]. Faseb J,2002,16(6):604-6.
[56] Uva BM, Masini MA, Sturla M, et al. Microgravity-induced apoptosis incultured glial cells[J]. Eur J Histochem,2002,46(3):209-14.
[57] Grimm D, Kossmehl P, Shakibaei M, et al. Effects of simulated microgravityon thyroid carcinoma cells[J]. J Gravit Physiol,2002,9(1):P253-6.
[58] Boonyaratanakornkit JB, Cogoli A, Li CF, et al. Key gravity-sensitivesignaling pathways drive T cell activation[J]. Faseb J,2005,19(14):2020-2.
[59] Maccarrone M, Battista N, Meloni M, et al. Creating conditions similar tothose that occur during exposure of cells to microgravity induces apoptosis inhuman lymphocytes by5-lipoxygenase-mediated mitochondrial uncouplingand cytochrome c release[J]. J Leukoc Biol,2003,73(4):472-81.
[60] Cooper D, Pellis NR. Suppressed PHA activation of T lymphocytes insimulated microgravity is restored by direct activation of protein kinase C[J].J Leukoc Biol,1998,63(5):550-62.
[61] Schmitt DA, Hatton JP, Emond C, et al. The distribution of protein kinase Cin human leukocytes is altered in microgravity[J]. Faseb J,1996,10(14):1627-34.
[62] Hatton JP, Gaubert F, Cazenave JP, et al. Microgravity modifies proteinkinase C isoform translocation in the human monocytic cell line U937andhuman peripheral blood T-cells[J]. J Cell Biochem,2002,87(1):39-50.
[63] Kossmehl P, Shakibaei M, Cogoli A, et al. Simulated microgravity inducesprogrammed cell death in human thyroid carcinoma cells[J]. J Gravit Physiol,2002,9(1):P295-6.
[64] Nakamura H, Kumei Y, Morita S, et al. Antagonism between apoptotic(Bax/Bcl-2) and anti-apoptotic (IAP) signals in human osteoblastic cellsunder vector-averaged gravity condition[J]. Ann N Y Acad Sci,2003,1010:143-7.
[65] Loesberg WA, Walboomers XF, Van Loon JJ, et al. Simulated microgravityactivates MAPK pathways in fibroblasts cultured on microgrooved surfacetopography[J]. Cell Motil Cytoskeleton,2008,65(2):116-29.
[66] Grigoryan EN, Anton HJ, Mitashov VI. Microgravity effects on neural retinaregeneration in the newt[J]. Adv Space Res,1998,22(2):293-301.
[67] Grigoryan EN, Mitashov VI, Anton HJ. Urodelean amphibians in studies onmicrogravity: effects upon organ and tissue regeneration[J]. Adv Space Res,2002,30(4):757-64.
[68] Anton HJ, Koussoulakos S. Unilateral forelimb amputation affects proteinsynthesis in ipsilateral and contralateral spinal cord and spinal ganglianeurons of the newt in vivo[J]. Dev Neurosci,1993,15(2):121-7.
[69] Grigoryan EN, Anton HJ, Mitashov VI. Real and simulated microgravity canactivate signals stimulating cells to enter the S phase during lens regenerationin urodelean amphibians[J]. Advances in Space Research,2006,38(6):1071-8.
[70] Li S, Ma Z, Niu Z, et al. NASA-approved rotary bioreactor enhancesproliferation and osteogenesis of human periodontal ligament stem cells[J].Stem Cells Dev,2009,18(9):1273-82.
[71] Slentz DH, Truskey GA, Kraus WE. Effects of chronic exposure to simulatedmicrogravity on skeletal muscle cell proliferation and differentiation[J]. InVitro Cell Dev Biol Anim,2001,37(3):148-56.
[72] Unsworth BR, Lelkes PI. Growing tissues in microgravity[J]. Nat Med,1998,4(8):901-7.
[73] Plett PA, Frankovitz SM, Abonour R, et al. Proliferation of humanhematopoietic bone marrow cells in simulated microgravity[J]. In Vitro CellDev Biol Anim,2001,37(2):73-8.
[74] Chiu B, Wan JZ, Abley D, et al. Induction of vascular endothelial phenotypeand cellular proliferation from human cord blood stem cells cultured insimulated microgravity[J]. Acta Astronaut,2005,56(9-12):918-22.
[75] Li J, Zhang S, Chen J, et al. Modeled microgravity causes changes in thecytoskeleton and focal adhesions, and decreases in migration in malignanthuman MCF-7cells[J]. Protoplasma,2009,238(1-4):23-33.
[76]岳茗，张小铀，丁柏，等.模拟失重对培养心肌细胞形态和结构的影响[J].空间科学学报，1998，18(1):75-80.
[77]李莹辉，丁柏，汪恭质，等.药物对模拟失重条件下心肌细胞功能的保护作用[J].航天医学与医学工程，1999，17(5):326-8.
[78] Lecina M, Ting S, Choo A, et al. Scalable platform for human embryonicstem cell differentiation to cardiomyocytes in suspended microcarriercultures[J]. Tissue Eng Part C Methods,2011,16(6):1609-19.
[79] Shimada N, Sokunbi G, Moorman SJ. Changes in gravitational force affectgene expression in developing organ systems at different developmentaltimes[J]. BMC Dev Biol,2005,5:10.
[80] Morey-Holton ER, Globus RK. Hindlimb unloading rodent model: technicalaspects[J]. J Appl Physiol,2002,92(4):1367-77.
[81] Musacchia XJ, Fagette S. Weightlessness simulations for cardiovascular andmuscle systems: validity of rat models[J]. J Gravit Physiol,1997,4(3):49-59.
[82] Zhang LF. Vascular adaptation to microgravity: what have we learned[J]? JAppl Physiol,2001,91(6):2415-30.
[83] Zhang LF, Cheng JH, Liu X, et al. Cardiovascular changes of conscious ratsafter simulated microgravity with and without daily-Gx gravitation[J]. J ApplPhysiol,2008,105(4):1134-45.
[84] Powers J, Bernstein D. The mouse as a model of cardiovascular adaptations tomicrogravity[J]. J Appl Physiol,2004,97(5):1686-92.
[85] Somody L, Fagette S, Frutoso J, et al. Recording heart rate and blood pressurein rats during parabolic flight[J]. Life Sci,1998,63(10):851-7.
[86] Verheyden B, Liu J, Beckers F, et al. Adaptation of heart rate and bloodpressure to short and long duration space missions[J]. Respir PhysiolNeurobiol,2009,169Suppl1:S13-6.
[87] Grenon SM, Xiao X, Hurwitz S, et al. Simulated microgravity inducesmicrovolt T wave alternans[J]. Ann Noninvasive Electrocardiol,2005,10(3):363-70.
[88] Tank J, Baevsky RM, Funtova, II, et al. Orthostatic heart rate responses afterprolonged space flights[J]. Clin Auton Res,2011,21(2):121-4.
[89] JB C, MW B, w F. Cardiopulmonary function. In:Nicogossian A, Huntoon C,Pool S (eds): Spcace Physiology and Medicine,3rd Edition[J]. Philadelpha,Lea&Febiger1994:286-304.
[90] WR H, JF Z. Clinical aspects of crew health. In: Johnston R, Dietein LD,Berry CA (eds.): Biomedical Results of Apollo (NASA SP-368),SectionII,Chapter1[J]. Washington DC,1995.
[91] Douglas WR. Current status of space medicine and exobiology[J]. AviatSpace Environ Med,1978,49(7):902-4.
[92] R S, K S, D S, et al. Vectorcardiographic changes during extended spaceflight (M093): Observations at rest and during exercise. In: Johnson RS,Dietlein LF (eds): Biomedical Results of Skylab (NASA SP-377), Section V,Chapter33[C]. Washinton DC.1977.
[93] Bungo MW, Johnson PC, Jr. Cardiovascular examinations and observations ofdeconditioning during the space shuttle orbital flight test program[J]. AviatSpace Environ Med,1983,54(11):1001-4.
[94] Fritsch-Yelle JM, Leuenberger UA, D'Aunno DS. An episode of ventriculartachycardia during long-duration spaceflight[J]. Am J Cardiol,1998,81(11):1391-2.
[95] D'Aunno DS, Dougherty AH, DeBlock HF. Effect of short-and long-durationspaceflight on QTc intervals in healthy astronauts[J]. Am J Cardiol,2003,91(4):494-7.
[96] Rossum AC, Wood ML, Bishop SL, et al. Evaluation of cardiac rhythmdisturbances during extravehicular activity[J]. Am J Cardiol,1997,79(8):1153-5.
[97] Martin DS, South DA, Wood ML, et al. Comparison of echocardiographicchanges after short-and long-duration spaceflight[J]. Aviat Space EnvironMed,2002,73(6):532-6.
[98] Bungo MW, Goldwater DJ, Popp RL, et al. Echocardiographic evaluation ofspace shuttle crewmembers[J]. J Appl Physiol,1987,62(1):278-83.
[99] Schlagheck RA, Trach BL. Microgravity research results and experiencesfrom the NASA/MIR space station program[J]. Acta Astronautica,2003,53(12):983-96.
[100] Rummell JA, Sawin CF, Buderer MC, et al. Physiological response toexercise after space flight--Apollo14through Apollo17[J]. Aviat SpaceEnviron Med,1975,46(5):679-83.
[101] Smith RF, Stanton K, Stoop D, et al. Quantitative electrocardiography duringextended space flight[J]. Acta Astronaut,1975,2(1-2):89-102.
[102] Martin DS, South DA, Garcia KM, et al. Ultrasound in space[J]. UltrasoundMed Biol,2003,29(1):1-12.
[103] Dorfman TA, Levine BD, Tillery T, et al. Cardiac atrophy in womenfollowing bed rest[J]. J Appl Physiol,2007,103(1):8-16.
[104] Yu ZB, Bao JX, Ma J, et al. Changes in myocardial contractility andcontractile proteins after four weeks of simulated [correction of simulate]weightlessness in rats[J]. J Gravit Physiol,2000,7(2):P147-8.
[105] Tuday EC, Berkowitz DE. Microgravity and cardiac atrophy: no sexdiscrimination[J]. J Appl Physiol,2007,103(1):1-2.
[106] Riley DA, Thompson JL, Krippendorf BB. Review of spaceflight andhindlimb suspension unloading induced sarcomere damage and repair[J].Basic Appl Myol,1995,5(2):139-45.
[107] Rokhlenko KD, Mul'diiarov P. Myocardial ultrastructure of rats exposedaboard biosatellite "Cosmos-936"[J]. Kosm Biol Aviakosm Med,1981,15(1):77-82.
[108] Thomason DB, Anderson O, Menon V, et al. Fractal analysis of cytoskeletonrearrangement in cardiac muscle during head-down tilt[J]. J Appl Physiol,1996,81(4):1522-7.
[109] Connor MK, Hood DA. Effect of microgravity on the expression ofmitochondrial enzymes in rat cardiac and skeletal muscles[J]. J Appl Physiol,1998,84(2):593-8.
[110] Perhonen MA, Franco F, Lane LD, et al. Cardiac atrophy after bed rest andspaceflight[J]. J Appl Physiol,2001,91(2):645-53.
[111] Fen Y, Hui LY, Bai D, et al. Reduced function and disassembledmicrotubules of cultured cardiomyocytes in spaceflight[J]. Chinese ScienceBulletin,2008,53(8):1185-92.
[112] Yao YH, Xiong JH, Liang ZG, et al. Gray characteristic analysis ofmicrotubules in cardiac myocytes[J]. Space Med Med Eng (Beijing),2004,17(5):322-5.
[113] Kwon O, Tranter M, Jones WK, et al. Differential translocation of nuclearfactor-kappaB in a cardiac muscle cell line under gravitational changes[J]. JBiomech Eng,2009,131(6):064503.
[114] Hayden MS, Ghosh S. Signaling to NF-kappaB[J]. Genes Dev,2004,18(18):2195-224.
[115] Mercurio F, Manning AM. NF-kappaB as a primary regulator of the stressresponse[J]. Oncogene,1999,18(45):6163-71.
[116] Jones WK, Brown M, Wilhide M, et al. NF-kappaB in cardiovascular disease:diverse and specific effects of a "general" transcription factor[J]?Cardiovasc Toxicol,2005,5(2):183-202.
[117] Gordon JW, Shaw JA, Kirshenbaum LA. Multiple facets of NF-kappaB inthe heart: to be or not to NF-kappaB[J]. Circ Res,2011,108(9):1122-32.
[118] Guttridge DC, Mayo MW, Madrid LV, et al. NF-kappaB-induced loss ofMyoD messenger RNA: possible role in muscle decay and cachexia[J].Science,2000,289(5488):2363-6.
[119] Ladner KJ, Caligiuri MA, Guttridge DC. Tumor necrosis factor-regulatedbiphasic activation of NF-kappa B is required for cytokine-induced loss ofskeletal muscle gene products[J]. J Biol Chem,2003,278(4):2294-303.
[120] Hunter RB, Stevenson E, Koncarevic A, et al. Activation of an alternativeNF-kappaB pathway in skeletal muscle during disuse atrophy[J]. Faseb J,2002,16(6):529-38.
[121] Lawler JM, Song W, Demaree SR. Hindlimb unloading increases oxidativestress and disrupts antioxidant capacity in skeletal muscle[J]. Free RadicBiol Med,2003,35(1):9-16.
[122] Li YP, Chen Y, Li AS, et al. Hydrogen peroxide stimulatesubiquitinconjugating activity and expression of genes for specific E2and E3proteins in skeletal muscle myotubes[J]. Am J Physiol Cell Physiol,2003,285(4):C806-12.
[123] Liu Y, Shen T, Randall WR, et al. Signaling pathways in activity-dependentfiber type plasticity in adult skeletal muscle[J]. J Muscle Res Cell Motil,2005,26(1):13-21.
[124] Childs TE, Spangenburg EE, Vyas DR, et al. Temporal alterations in proteinsignaling cascades during recovery from muscle atrophy[J]. Am J PhysiolCell Physiol,2003,285(2):C391-8.
[125] Zhang P, Chen X, Fan M. Signaling mechanisms involved in disuse muscleatrophy[J]. Med Hypotheses,2007,69(2):310-21.
[126] Gustafsson T, Osterlund T, Flanagan JN, et al. Effects of3days unloadingon molecular regulators of muscle size in humans[J]. J Appl Physiol,2010,109(3):721-7.
[127] Dodd SL, Hain B, Senf SM, Judge AR. Hsp27inhibits IKKbeta-inducedNF-kappaB activity and skeletal muscle atrophy[J]. Faseb J,2009,23(10):3415-23.
[128] Petersen LG, Damgaard M, Petersen JC, et al. Mechanisms of increase incardiac output during acute weightlessness in humans[J]. J Appl Physiol,2011,111(2):407-11.
[129] Convertino VA, Polet JL, Engelke KA, et al. Evidence for increasedbeta-adrenoreceptor responsiveness induced by14days of simulatedmicrogravity in humans[J]. Am J Physiol,1997,273(1Pt2):R93-9.
[130] Martel E, Champeroux P, Lacolley P, et al. Central hypervolemia in theconscious rat: a model of cardiovascular deconditioning[J]. J Appl Physiol,1996,80(4):1390-6.
[131] Shellock FG, Swan HJ, Rubin SA. Early central venous pressure changes inthe rat during two different levels of head-down suspension[J]. Aviat SpaceEnviron Med,1985,56(8):791-5.
[132] Deavers DR, Musacchia XJ, Meininger GA. Model for antiorthostatichypokinesia: head-down tilt effects on water and salt excretion[J]. J ApplPhysiol,1980,49(4):576-82.
[133] Dunn CD, Johnson PC, Lange RD. Regulation of hematopoiesis in ratsexposed to antiorthostatic hypokinetic/hypodynamia: II. Mechanisms of the"anemia"[J]. Aviat Space Environ Med,1986,57(1):36-44.
[134] Gardner LB, Preston RA. University of Miami Division of ClinicalPharmacology Therapeutic Rounds: the water-intolerant patient andperioperative hyponatremia[J]. Am J Ther,2000,7(1):23-30.
[135] Desplanches D, Mayet MH, Sempore B, et al. Effect of spontaneousrecovery or retraining after hindlimb suspension on aerobic capacity[J]. JAppl Physiol,1987,63(5):1739-43.
[136] Overton JM, Woodman CR, Tipton CM. Effect of hindlimb suspension onVO2max and regional blood flow responses to exercise[J]. J Appl Physiol,1989,66(2):653-9.
[137] Woodman CR, Sebastian LA, Tipton CM. Influence of simulatedmicrogravity on cardiac output and blood flow distribution duringexercise[J]. J Appl Physiol,1995,79(5):1762-8.
[138] Yu ZB, Zhang LF, Jin JP. A proteolytic NH2-terminal truncation of cardiactroponin I that is up-regulated in simulated microgravity[J]. J Biol Chem,2001,276(19):15753-60.
[139] Convertino VA, Bloomfield SA, Greenleaf JE. An overview of the issues:physiological effects of bed rest and restricted physical activity[J]. Med SciSports Exerc,1997,29(2):187-90.
[140] Galvez AS, Diwan A, Odley AM, et al. Cardiomyocyte degeneration withcalpain deficiency reveals a critical role in protein homeostasis[J]. Circ Res,2007,100(7):1071-8.
[141] Razeghi P, Volpini KC, Wang ME, et al. Mechanical unloading of the heartactivates the calpain system[J]. J Mol Cell Cardiol,2007,42(2):449-52.
[142] Fagette S, Somody L, Bouzeghrane F, et al. Biochemical characteristics ofbeta-adrenoceptors in rats after an18-day spaceflight (LMS-STS78)[J].Aviat Space Environ Med,1999,70(10):1025-8.
[143] Li Y, Arnold JM, Pampillo M, et al. Taurine prevents cardiomyocyte deathby inhibiting NADPH oxidase-mediated calpain activation[J]. Free RadicBiol Med,2009,46(1):51-61.
[144] Chen M, He H, Zhan S, et al. Bid is cleaved by calpain to an activefragment in vitro and during myocardial ischemia/reperfusion[J]. J BiolChem,2001,276(33):30724-8.
[145] Li Y, Li Y, Feng Q, et al. Calpain activation contributes to hyperglycaemiainduced apoptosis in cardiomyocytes[J]. Cardiovasc Res,2009,84(1):100-10.
[146] Hikoso S, Ikeda Y, Yamaguchi O, et al. Progression of heart failure wassuppressed by inhibition of apoptosis signal-regulating kinase1viatranscoronary gene transfer[J]. J Am Coll Cardiol,2007,50(5):453-62.
[147] Gorza L, Menabo R, Di Lisa F, et al. Troponin T cross-linking in humanapoptotic cardiomyocytes[J]. Am J Pathol,1997,150(6):2087-97.
[148] Singh RB, Chohan PK, Dhalla NS, et al. The sarcoplasmic reticulumproteins are targets for calpain action in the ischemic-reperfused heart[J]. JMol Cell Cardiol2004;37(1):101-10.
[149] Bajaj G, Sharma RK. TNF-alpha-mediated cardiomyocyte apoptosis involvescaspase-12and calpain[J]. Biochem Biophys Res Commun,2006,345(4):1558-64.
[150] Chang H, Zhang L, Xu PT, et al. Nuclear translocation of calpain-2regulatespropensity toward apoptosis in cardiomyocytes of tail-suspended rats[J]. JCell Biochem,2011,112(2):571-80.
[151]熊江辉，李莹辉，聂捷琳.模拟微重力效应对心肌细胞一氧化氮水平的影响及其相关机制的研究[J].中国科学，2002，32(6):568-73.
[152] Moibenko OO, Sahach VF, Tkachenko MM, et al. Mechanisms of nitricoxide activity in cardiovascular system as a basis of pathogenetic therapy ofrelated diseases[J]. Fiziol Zh,2004,50(1):11-30.
[153] Dupont E, Cieniewski-Bernard C, Bastide B, et al. Electrostimulation duringhindlimb unloading modulates PI3K-AKT downstream targets withoutpreventing soleus atrophy and restores slow phenotype through ERK[J]. AmJ Physiol Regul Integr Comp Physiol,2011,300(2):R408-17.
[154] Siamwala JH, Majumder S, Tamilarasan KP, et al. Simulated microgravitypromotes nitric oxide-supported angiogenesis via the iNOS-cGMP-PKGpathway in macrovascular endothelial cells[J]. FEBS Lett,2010,584(15):3415-23.
[155]刘朝霞,李志力,汪德生,等.模拟失重对大鼠心肌组织缝隙连接蛋白表达谱的影响[J].航天医学与医学工程,2008,21(1):6-10.
[156] Xia Y, Gong KZ, Xu M, et al Regulation of gap-junction protein connexin43by beta-adrenergic receptor stimulation in rat cardiomyocytes[J]. ActaPharmacol Sin,2009,30(7):928-34.
[157] Merrill AH Jr., Wang E, Mullins RE, et al. Analyses of plasma for metabolicand hormonal changes in rats flown aboard COSMOS2044[J]. J ApplPhysiol,1992,73(2Suppl):132S-5S.
[158] Miu B, Martin TP, Roy RR, et al. Metabolic and morphologic properties ofsingle muscle fibers in the rat after spaceflight, Cosmos1887[J]. Faseb J,1990,4(1):64-72.
[159] Fareh J, Bayard B, Gabrion J, et al. Cardiac and plasma atrial natriureticpeptide after9-day hindlimb suspension in rats[J]. J Appl Physiol,1994,76(2):641-9.
[160] Menon V, Thomason DB. Head-down tilt increases rat cardiac muscle eIF-2alpha phosphorylation[J]. Am J Physiol,1995,269(3Pt1):C802-4.
[161] J C, LF Z, J M, et al. Ultrastructural changes of myocardium in long termtailsuspended rats[J]. Chin J Aviat Med,1995,6(3):133-7.
[162] C L, LF Z, QW M, et al. Changes of type Ⅰand type Ⅲcollagens in ratmyocardium after medium or long term simulated weightlessness[J]. Chin JAerospace Med,2000,11(1):39-42.
[163] Yang CB, Wang YC, Gao Y, Geng J, et al. Artificial gravity with ergometricexercise preserves the cardiac, but not cerebrovascular, functions during4days of head-down bed rest[J]. Cytokine,2011,56(3):648-55.
[164] Coupe M, Yuan M, Demiot C, et al. Low-magnitude whole body vibrationwith resistive exercise as a countermeasure against cardiovasculardeconditioning after60days of head-down bed rest[J]. Am J Physiol RegulIntegr Comp Physiol,2011,301(6):R1748-54.
[165] Wang YC, Yang CB, Wu YH, et al. Artificial gravity with ergometricexercise as a countermeasure against cardiovascular deconditioning during4days of head-down bed rest in humans[J]. Eur J Appl Physiol,2011,111(9):2315-25.
[166]宝珍，李勇枝，辛冰牧，等.药复方对尾吊大鼠心肌ATP酶、SDH和能荷值的影响[J].航天医学与医学工程，2004，17(5):326-8.
[167]张文辉，亓鹏，杨芬，等.地高辛对模拟失重后大鼠心室功能的影响[J].航天医学与医学工程，2008，21(2):93-6.
[168] Rose EA, Gelijns AC, Moskowitz AJ, et al. Long-term use of a leftventricular assist device for end-stage heart failure[J]. N Engl J Med,2001,345(20):1435-43.
[169] Elsdale T, Bard J. Collagen substrata for studies on cell behavior[J]. J CellBiol,1972,54(3):626-37.
[170] McGuigan AP, Bruzewicz DA, Glavan A, et al. Cell encapsulation insub-mm sized gel modules using replica molding[J]. PLoS One,2008,3(5):e2258.
[171] Hunt NC, Grover LM. Cell encapsulation using biopolymer gels forregenerative medicine[J]. Biotechnol Lett,2010,32(6):733-42.
[172] Karp JM, Yeh J, Eng G, et al. Controlling size, shape and homogeneity ofembryoid bodies using poly(ethylene glycol) microwells[J]. Lab Chip,2007,7(6):786-94.
[173] Soranzo C, Della Torre G, Ingrosso A. Formation, growth and morphology ofmulticellular tumor spheroids from a human colon carcinoma cell line(LoVo)[J]. Tumori,1986,72(5):459-67.
[174] Dhiman HK, Ray AR, Panda AK. Characterization and evaluation ofchitosan matrix for in vitro growth of MCF-7breast cancer cell lines[J].Biomaterials,2004,25(21):5147-54.
[175] Cukierman E, Pankov R, Yamada KM. Cell interactions withthree-dimensional matrices[J]. Curr Opin Cell Biol,2002,14(5):633-9.
[176] Cukierman E, Pankov R, Stevens DR, et al. Taking cell-matrix adhesions tothe third dimension[J]. Science,2001,294(5547):1708-12.
[177] Alsberg E, Kong HJ, Hirano Y, et al. Regulating bone formation viacontrolled scaffold degradation[J]. J Dent Res,2003,82(11):903-8.
[178] Wu YM, Tang J, Zhao P, et al. Morphological changes and molecularexpressions of hepatocellular carcinoma cells in three-dimensional culturemodel[J]. Exp Mol Pathol2009;87(2):133-40.
[179] Hunt NC, Grover LM. Cell encapsulation using biopolymer gels forregenerative medicine[J]. Biotechnol Lett,2010,32(6):733-42.
[180] Elliott NT, Yuan F. A review of three-dimensional in vitro tissue models fordrug discovery and transport studies[J]. J Pharm Sci,2010,100(1):59-74.
[181] Yamada KM, Cukierman E. Modeling tissue morphogenesis and cancer in3D[J]. Cell,2007,130(4):601-10.
[182] Engler AJ, Carag-Krieger C, Johnson CP, et al. Embryonic cardiomyocytesbeat best on a matrix with heart-like elasticity: scar-like rigidity inhibitsbeating[J]. J Cell Sci,2008,121(Pt22):3794-802.
[183] Discher DE, Mooney DJ, Zandstra PW. Growth factors, matrices, and forcescombine and control stem cells[J]. Science,2009,324(5935):1673-7.
[184] Mitragotri S, Lahann J. Physical approaches to biomaterial design[J]. NatMater,2009,8(1):15-23.
[185] Griffith LG, Swartz MA. Capturing complex3D tissue physiology in vitro[J].Nat Rev Mol Cell Biol,2006,7(3):211-24.
[186] Braccini A, Wendt D, Jaquiery C, et al. Three-dimensional perfusion cultureof human bone marrow cells and generation of osteoinductive grafts[J].Stem Cells,2005,23(8):1066-72.
[187] Guthke R, Zeilinger K, Sickinger S, et al. Dynamics of amino acidmetabolism of primary human liver cells in3D bioreactors[J]. BioprocessBiosyst Eng,2006,28(5):331-40.
[188] Pomahac B, Svensjo T, Yao F, et al. Tissue engineering of skin[J]. Crit RevOral Biol Med,1998,9(3):333-44.
[189] Bartholoma P, Gorjup E, Monz D, et al. Three-dimensional in vitroreaggregates of embryonic cardiomyocytes: a potential model system formonitoring effects of bioactive agents[J]. J Biomol Screen,2005,10(8):814-22.
[190] Borg TK, Baudino TA. Dynamic interactions between the cellularcomponents of the heart and the extracellular matrix[J]. Pflugers Arch,2011,462(1):69-74.
[191] Bursac N, Papadaki M, Cohen RJ, et al. Cardiac muscle tissue engineering:toward an in vitro model for electrophysiological studies[J]. Am J Physiol1999;277(2Pt2):H433-44.
[192]司徒镇强.细胞培养.世界图书出版公司[M].2007:107-8.
[194] Kofidis T, Akhyari P, Boublik J, et al. In vitro engineering of heart muscle:artificial myocardial tissue[J]. J Thorac Cardiovasc Surg2002;124(1):63-9.
[193] Wakabayashi S, Pang T, Su X, et al. A novel topology model of the humanNa(+)/H(+) exchanger isoform1[J]. J Biol Chem2000;275(11):7942-9.
[194] Bucaro MA, Zahm AM, Risbud MV, et al. The effect of simulatedmicrogravity on osteoblasts is independent of the induction of apoptosis[J].J Cell Biochem,2007,102(2):483-95.
[195] Vassy J, Portet S, Beil M, et al. Weightlessness acts on human breast cancercell line MCF-7[J]. Space Life Sciences: Gravitational Biology,2003,32(8):1595-603.
[196] Qian AR, Zhang W, Xie L, et al. Simulated weightlessness alters biologicalcharacteristics of human breast cancer cell line MCF-7[J]. Acta Astronautica,2008,63(7-10):947-58.
[197] Swayne TC, Boldogh IR, Pon LA. Imaging of the cytoskeleton andmitochondria in fixed budding yeast cells[J]. Methods Mol Biol,2009,586:171-84.
[198] Hong-xia Z, Wei-ming T, Lei Y, et al. Effect of simulated weightlessness onspindle apparatus structure and cell cycle of NIH3T3fibroblasts[J]. SpaceMedicine&Medical Engineering,2010,23(6):416-8.
[199] Zimmermann WH, Eschenhagen T. Embryonic stem cells for cardiac muscleengineering[J]. Trends Cardiovasc Med,2007,17(4):134-40.
[200] Ott HC, Davis BH, Taylor DA. Cell therapy for heart failure--muscle, bonemarrow, blood, and cardiac-derived stem cells[J]. Semin Thorac CardiovascSurg,2005,17(4):348-60.
[201] Lazerges M. Selective hypergravity stimulation: its effects on the humanbalance and gait functions. A model to assess, in normal gravity conditions,some aspects of the perturbations induced on human body by microgravityconditions[J]. Acta Astronaut,1990,22:375-80.
[202] Sumanasekera WK, Zhao L, Ivanova M, et al. Effect of estradiol anddihydrotestosterone on hypergravity-induced MAPK signaling and occludinexpression in human umbilical vein endothelial cells[J]. Cell Tissue Res,2006,324(2):243-53.
[203] Masini MA, Prato P, Scarabelli L, et al. In vitro effects of simulatedmicrogravity on Sertoli cell function[J]. Advances in Space Research,2011,47(4):575-81.
[204] Bucaro MA, Fertala J, Adams CS, et al. Bone cell survival in microgravity:evidence that modeled microgravity increases osteoblast sensitivity toapoptogens[J]. Ann N Y Acad Sci,2004,1027:64-73.
[205] Infanger M, Kossmehl P, Shakibaei M, et al. Simulated weightlessnesschanges the cytoskeleton and extracellular matrix proteins in papillarythyroid carcinoma cells[J]. Cell Tissue Res,2006,324(2):267-77.
[206] Kumei Y, Morita S, Katano H, et al. Microgravity signal ensnarls celladhesion, cytoskeleton, and matrix proteins of rat osteoblasts: osteopontin,CD44, osteonectin, and alpha-tubulin[J]. Ann N Y Acad Sci,2006,1090:311-7.
[207] klaus Legner. humans in space and space biology[C]. Austria,2011,77-13
[208]杨芬，李莹辉，丁柏.空间飞行条件下心肌细胞发生功能减退与微管解聚[J].科学通报，2008，53(5):561-7.
[209] Akins RE, Schroedl NA, Gonda SR, et al. Neonatal rat heart cells cultured insimulated microgravity[J]. In Vitro Cell Dev Biol Anim,1997,33(5):337-43.
[210] White RJ, Blomqvist CG. Central venous pressure and cardiac functionduring spaceflight[J]. J Appl Physiol,1998,85(2):738-46.
[211] Ray CA, Vasques M, Miller TA, et al. Effect of short-term microgravity andlong-term hindlimb unloading on rat cardiac mass and function[J]. J ApplPhysiol,2001,91(3):1207-13.
[212] Kanno S, Saffitz JE. The role of myocardial gap junctions in electricalconduction and arrhythmogenesis[J]. Cardiovasc Pathol,2001,10(4):169-77.
[213] Boengler K. Stimulation of cardiac beta-adrenoceptors targets connexin43[J]. Br J Pharmacol,2009,158(1):195-7.
[214] Kjenseth A, Fykerud T, Rivedal E, et al. Regulation of gap junctionintercellular communication by the ubiquitin system[J]. Cell Signal,2010,22(9):1267-73.
[215] Mehta PK, Griendling KK. Angiotensin II cell signaling: physiological andpathological effects in the cardiovascular system[J]. Am J Physiol CellPhysiol,2007,292(1):C82-97.
[216] Xue JH, Wang XC, Gao F, et al. Short-term simulated weightlessnessenhances response of L-type calcium channel to angiotensin II in cerebralvascular smooth muscle cells in rats[J]. Sheng Li Xue Bao,2011,63(1):81-8.
[217] Glitsch HG. Electrophysiology of the sodium-potassium-ATPase in cardiaccells. Physiol Rev,2001,81(4):1791-826.
[218] Tyapkina O, Volkov E, Nurullin L, et al. Resting membrane potential andNa+,K+-ATPase of rat fast and slow muscles during modeling ofhypogravity[J]. Physiol Res,2009,58(4):599-603.
[219] Swift F, Tovsrud N, Enger UH, et al. The Na+/K+-ATPase alpha2-isoformregulates cardiac contractility in rat cardiomyocytes[J]. Cardiovasc Res,2007,75(1):109-17.
[220] Al-Khalili L, Kotova O, Tsuchida H, et al. ERK1/2mediates insulin stimulation ofNa(+),K(+)-ATPase by phosphorylation of the alpha-subunit in human skeletal musclecells[J]. J Biol Chem,2004,279(24):25211-8.
[221] Wakabayashi S, Pang T, Su X, et al. Second mutations rescue point mutantof the Na(+)/H(+) exchanger NHE1showing defective surface expression[J].FEBS Lett,2000,487(2):257-61.
[222] Xue JH, Zhang LF, Ma J, Xie MJ. Differential regulation of L-type Ca2+channels in cerebral and mesenteric arteries after simulated microgravity inrats and its intervention by standing[J]. Am J Physiol Heart Circ Physiol,2007,293(1):H691-701.
[223] Shenkman BS, Nemirovskaya TL. Calcium-dependent signaling mechanismsand soleus fiber remodeling under gravitational unloading[J]. J Muscle ResCell Motil,2008,29(6-8):221-30.
[224] Nattel S, Li D. Ionic remodeling in the heart: pathophysiologicalsignificance and new therapeutic opportunities for atrial fibrillation[J]. CircRes,2000,87(6):440-7.
[225] Iwasaki YK, Yamashita T, Sekiguchi A, et al. A method for the simultaneousanalysis of mRNA levels of multiple cardiac ion channels with a multi-probeRNase protection assay[J]. Europace,2006,8(11):1011-5.
[226] Tsutsui H. Mitochondrial oxidative stress and heart failure[J]. Intern Med,2006,45(13):809-13.
[227] Majumder S, Siamwala JH, Srinivasan S, et al. Simulated microgravitypromoted differentiation of bipotential murine oval liver stem cells bymodulating BMP4/Notch1signaling[J]. J Cell Biochem,2011,112(7):1898-908.
[228] Li GB, Liu YD, Wang GH, et al. Reactive oxygen species and antioxidantenzymes activity of Anabaena sp. PCC7120(Cyanobacterium) undersimulated microgravity[J]. Acta Astronaut,2004,55(11):953-7.
[229] Wang J, Zhang J, Bai S, et al. Simulated microgravity promotes cellularsenescence via oxidant stress in rat PC12cells[J]. Neurochem Int,2009,55(7):710-6.
[230] Coletta DK, Mandarino LJ. Mitochondrial dysfunction and insulin resistancefrom the outside in: extracellular matrix, the cytoskeleton, andmitochondria[J]. Am J Physiol Endocrinol Metab,2011,301(5):E749-55.
[231] Belch JJ, Bridges AB, Scott N, et al. Oxygen free radicals and congestiveheart failure[J]. Br Heart J,1991,65(5):245-8.
[232] Hill MF, Singal PK. Antioxidant and oxidative stress changes during heartfailure subsequent to myocardial infarction in rats[J]. Am J Pathol,1996,148(1):291-300.
[233] Borchi E, Bargelli V, Stillitano F, et al. Enhanced ROS production byNADPH oxidase is correlated to changes in antioxidant enzyme activity inhuman heart failure[J]. Biochim Biophys Acta,2010,1802(3):331-8.
[234] Josephson RA, Silverman HS, Lakatta EG, et al. Study of the mechanisms ofhydrogen peroxide and hydroxyl free radical-induced cellular injury andcalcium overload in cardiac myocytes[J]. J Biol Chem,1991,266(4):2354-61.
[235] Ou Y, Liao GY, Wu WT. Potential use of hirudin in diabetic cataract: a studyof galactose mediated human lens epithelial cells injury[J]. Chem BiolInteract,2008,173(2):141-7.
[236] Iadecola C, Alexander M. Cerebral ischemia and inflammation[J]. Curr OpinNeurol,2001,14(1):89-94.
[237] Mattson MP. Neuronal life-and-death signaling, apoptosis, andneurodegenera-tive disorders[J]. Antioxid Redox Signal,2006,8(11-12):1997-2006.
[238] Mayer MP, Bukau B. Hsp70chaperones: cellular functions and molecularmechanism[J]. Cell Mol Life Sci,2005,62(6):670-84.
[239] Kalmar B, Greensmith L. Induction of heat shock proteins for protectionagainst oxidative stress[J]. Advanced Drug Delivery Reviews,2009,61(4):310-8.
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