Ⅰ.丹参酮ⅡA对压力超负荷大鼠心肌肥厚信号转导系统MAPK通路的影响 Ⅱ.缺血后适应方法对脑的保护作用及其在复苏中的应用研究
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摘要
[摘要]目的建立大鼠胸主动脉部分缩窄诱导心肌肥厚动物模型。方法雄性SD大鼠30只,随机分为两组：胸主动脉缩窄组20只和同期假手术组10只。在右无名动脉和左颈总动脉之间将主动脉结扎于8G针头上,随后将针头退出即可。术后10周,采用超声心动图检测心脏、观察心脏的大体剖面以及HE染色、测量心肌肥厚指数评价心肌肥厚的效果。结果术后10周,肉眼观：模型组心脏体积明显大于对照组。M型超声示：模型组较假手术组缩短分数下降,左室内径和室壁厚度明显增加。超声测量结果示：模型组与假手术组比较：室间隔厚度增加明显(2.527+0.269 vs.1.943+0.1) mm, (P<0.01);后壁厚度增加明显(2.492+0.242 vs.1.902+0.076)(P<0.01)；缩短分数略减小(49+7.681 vs.55.7+9.828)(P＞0.05)；左室舒张末期内径、左室收缩末期内径及射血分数均无明显变化。心脏肥厚指数明显增大(3.196+0.11 vs.1.785+0.099)P＜0.01。结论胸主动脉缩窄可以导致大鼠心肌肥厚,为研究心室肥厚、心肌功能障碍以及心肌重构提供了一个很好的模型。
目的探讨丹参酮ⅡA对大鼠胸主动脉缩窄诱导的心肌肥厚及MAPK(丝裂原活化蛋白激酶)信号转导通路的影响。方法通过在右无名动脉和左侧颈总动脉之间部分缩窄胸主动脉诱导大鼠心肌肥厚模型。将制好模型的大鼠随机分成6组：假手术组、胸主动脉缩窄组、胸主动脉缩窄组+低剂量丹参酮组(5mg/kg)、胸主动脉缩窄组+中剂量丹参酮组(10mg/kg)、胸主动脉缩窄组+高剂量丹参酮组(20mg/kg)、胸主动脉缩窄组+缬沙坦组(10mg/kg)。用药8周后,B超检测心肌肥厚程度和心功能的变化,将心肌样本沿横切面切开并做HE染色,Western blot法分析心肌MAPK信号蛋白表达变化。结果胸主动脉缩窄组相对于假手术组在心脏重量指数、左室重量指数、心肌纤维直径、左心室后壁及室间隔厚度均增加。而丹参酮ⅡA和缬沙坦组均可减轻上述变化的程度。Western blot结果显示：相对假手术组,模型组的p-ERK(磷酸化的细胞外信号调节激酶)和p-p38(磷酸化的p38丝裂原活化蛋白激酶)均减少,差异均具有统计学意义(均P<0.01)。相对于模型组,各丹参酮和缬沙坦治疗组p-ERK减少,差异均具有统计学意义(均P<0.05)；另外,丹参酮高剂量和中剂量组,以及缬沙坦治疗组p-p38增加,差异均具有统计学意义(均P<0.05)。结论丹参酮ⅡA通过调节MAPK通路中的蛋白表达而发挥其抑制心肌肥厚的作用。
目的研究缺血后适应对全脑缺血再灌注大鼠突触超微结构及突触素表达的影响。方法将动物随机分成3组(每组8只)：假手术组(C)、缺血再灌注组(Ⅰ)和缺血+后适应组(Post-con)。按照四血管阻塞法制作脑缺血模型：假手术组：分离动物颈总动脉,不阻断血流；缺血再灌注组：阻断双侧颈总动脉10min再灌注；缺血+后适应组：阻断双侧颈总动脉10min再灌注,于再灌注的初期给予15s灌注/15s夹闭,共三个循环的后适应。动物全脑缺血48h后断头处死,取海马组织包埋切片后,用透射电子显微镜观察海马CA1区神经元超微结构变化,并应用免疫组化和Westernblot方法观察突触素的表达。结果①电镜观察：缺血+后适应(Post-con)组与缺血再灌注(Ischemic)组相比,神经毡内突触数目较多,线粒体、突触损伤较轻。②免疫组化染色：缺血+后适应(Post-con)组与缺血再灌注(Ischemic)组相比,海马区突触素免疫活性增高,免疫产物的颗粒较大、密集、染色深；细胞排列较规则,细胞肿胀较轻。③Westernblot:缺血+后适应(Post-con)组与缺血再灌注(Ischemic)组相比,海马区突触素蛋白表达增高,三组比较差异有统计学意义(P<0.05)。结论缺血后适应可以减轻神经元的再灌注损伤,并通过调节神经元的可塑性,促进受损神经功能的恢复。
摘要现代心肺复苏技术的实施可以增加患者的自主循环恢复率并提高患者的入院率,但是患者的生存出院率却仍然不是很理想,主要原因为心跳骤停后的脑损伤。后适应现象的发现为我们打开了一扇通往内源性的神经保护之门。后适应的保护机制包括：在缺血再灌注时,减轻线粒体的钙超载和氧化应激、激活再灌注损伤救援激酶通路、预防线粒体通透性转运孔的开放。后适应的潜在临床应用优势在于能用于意外的或者是难以预测的缺血情况下的复灌。前期的实验研究显示后适应可以用于减轻突发性的冠状动脉阻塞、急性心梗以及中风后的缺血再灌注损伤。由于心跳骤停复苏时心脏和脑要面临与前述的疾病相似的病理生理过程,我们推测后适应原理同样可以用于心肺复苏的临床实践中来减轻心肺复苏后的脑损伤。我们提出了一种新的心肺复苏程序：后适应心脑复苏法。这种方法步骤为：先进行胸部按压18秒,停止按压10秒(进行通气),共3个循环。然后进行持续的胸部按压直到患者恢复自主循环。后适应心肺复苏法不仅可以为重要器官的提供血流,而且可以激活内源性的保护机制来减轻心跳骤停后的脑损伤。我们认为这个方法作为心肺复苏时脑保护的干预措施,能简单、安全、有效地预防和减轻心跳骤停后的脑损伤,改善心跳骤停的预后。
Objective To construct cardiac hypertrophy model by partially binding thoracic aorta in rats. Methods Thirty male Sprague Dawley(SD) rats were divided into sham surgery (n=10) and operation (n=20) randomly. Operation methods: The suture was snugly tied around the 22-gauge needle and the aorta which was between the origin of the right innominate and left common carotid arteries. After ligation, the needle was quickly removed. Echocardiography、the external appearance and HE staining was performed 10 weeks after the surgery. Results After 10 weeks, the volume of heart in operated rats is increased than sham-operation groups. Compared with the sham-operated, M-mode demonstrated that the operated group's left ventricle (LV) cavity and the posterior wall thickness increased markedly and its fractional shortening decreased. Compared with sham-operation groups, the operated rats showed that the interventricular septum thickness (2.527+0.269 vs.1.943+0.1, P<0.01),and the posterior wall thickness (2.492+0.242 vs.1.902+0.076, P<0.01) increased; the fractional shortening diminished(49+7.681 vs.55.7+9.828,P>0.05); the cardiac hypertrophy index increased (3.196+0.11 vs.1.785+0.099,P<0.01); the changes of LV internal diastolic dimension (LVIDd)、LV internal systolic dimension (LVIDs)and ejection fraction was not obvious. Conclusion Thoracic aorta constriction (TAC) induced rat cardiac hypertrophy will provide a reproducible model to study cardiac hypertrophy、myocardial dysfunction and myocardial remodeling.
Objective To determinate the effects of Sodium TanshinoneⅡA sulfonate (STS) on cardiomyocyte hypertrophy and explored the relative effects of STS on mitogen-activated protein kinase signal transduction system in rats with cardiomyocyte hypertrophy through constricting the thoracic aorta. Methods To make the models of cardiomyocyte hypertrophy in vivo, the thoracic aorta was partially tied between the right innominate and the left common carotid arteries. The rat randomly divided in 6 groups (n= 8/group) as follows:1) sham,2) transverse aortic constriction (TAC),3) TAC+Low-dose Tan (TAC+LT) (5mg/kg),4) TAC+ medium-dose Tan (TAC+MT) (10mg/kg),5)TAC+high-dose Tan (TAC+HT) (20mg/kg) and 6)TAC+Val (10mg/kg). After 8 week medication, Echocardiography was performed to measure the changes of hypertrophy and heart function, and heart samples were cut into transverse sections and stained with hematoxylin and eosin (H&E). The MAPKs protein expression in the cardiomyocytes was measured by western blot analysis. Results The heart weight index (HWI), left ventricular mass index (LVMI) and cross-sectional diameter of cardiomyocytes (CD), left ventricular posterior wall thickness (LVWT), interventricular septal thickness (IVS) were significantly increased than sham group as soon as 2 months post-TAC. And the relative parameters of STS groups and Val group were alleviated than the TAC group. Western blot analysis shows the p-ERK and p-p38 expression was significantly decreased in the TAC group compared with the sham group (p<0.01). The p-ERK expression was significantly decreased in the STS groups and Val group compared with the TAC group (p<0.05). The TAC+HT group, TAC+MT group and Val group had significantly higher p-p38 expression than the TAC group (p<0.05). Conclusion TanshinoneⅡA could regulate the expression of protein in MAPK pathway to exert it inhibition of hypertrophy of cardiomyocyte.
Objective:To study the effects of postconditioning on synaptic ultrastructure and synaptophysin expression in global cerebral ischemia reperfusion. Methods:To make the models of global cerebral ischemia in vivo,;the vertebral artery of rat were occluded and common their carotid arteries were transitorily cliped. The rats randomly divided in 3 groups (n= 8/group) as follows:1) control(C),2) ischemia reperfusion (I),3) ischemia+postconditioning (Post-con). Control group: beparated carotid artery and didnot blocked blood flow. Ischemia reperfusion group: bilateral carotid artery was occluded 10min then reperfusion. Ischemia+ postconditioning group:bilateral carotid artery was occluded 10min then executed postconditioning protocol (3 cycles of 15s reperfusion/15s clipping) before reperfusion. Fourty eight hours later the rat in 3 groups were killed and their brain tissues were harvested and made into slices, stained with immunohistochemical techniques, photographed under the transmission electron microscope and measured synaptophysin protein expression by western blot analysis. Results:①it was observed in the ischemia+postconditioning (Post-con) group from electric mirror that there were a relatively large number of synaptic neuropil, and the damages of mitochondria and synaptic were minor, compared with the ischemia-reperfusion (Ischemic) group,②ischemia+postconditioning (Post-con) group compared with the ischemia-reperfusion (Ischemic) group:The immunoreactivity of synaptophysin in the hippocampus increased significantly; the immune products were larger particles, dense and deeply stained; cells arranged in regular and cell swellings were less.③Western blot analysis show the synaptophysin expression was significantly increased in the Post-con group compared with the ischemic group (P<0.05). Conclusion:Postconditioning reduced reperfusion injury in neurons, regulated neuronal plasticity and promoted the recovery of nerve function.
Although current cardiopulmonary resuscitation (CPR) performance can increase the rates of restoration of spontaneous circulation (ROSC) and survival to hospital admission, the discharge rates of patients remain disappointing. The high mortality rate is attributed to post-cardiac arrest brain injury. The discovery of the postconditioning phenomenon opens a door to endogenous neuroprotection. The protection mechanisms of postconditioning include attenuating mitochondrial calcium overload and reducing oxidative stress, recruiting the reperfusion injury salvage kinase (RISK) pathway, and preventing from the mitochondrial permeability transition pore (mPTP) opening at the time of reperfusion. An advantage of postconditioning lies in the potentially clinical application in the unexpected ischemic situation. Prior laboratory researches indicate that postconditioning may lessen the reperfusion/ischemia-induced injury in unexpected coronary occlusion, acute myocardial infarction and stroke. Because cardiac arrest, stroke and acute myocardial infarction have a similar pathophysiological process, we hypothesize that postconditioning could be used in the clinical practice of CPR to treat patients with post-cardiac arrest brain injury. We propose a novel protocol of 'Postconditioning cardiocerebral resuscitation (Post-CCR)'. The Post-CCR includes applying three cycles of 18 seconds chest compression and 10 seconds interruption for ventilation first, and then executing chest compression only CPR until the patients return spontaneous circulation. Post-CCR can not only provide vital blood flow to the heart and brain but also activate endogenous protective mechanism to lessen post-cardiac arrest brain injury. We consider that it would become a feasible, safe and efficient cerebralprotective intervention in the prevention and alleviation of post-cardiac arrest brain injury, which would also improve the outcome after cardiac arrest.
目的探讨丹参酮ⅡA对大鼠胸主动脉缩窄诱导的心肌肥厚及MAPK(丝裂原活化蛋白激酶)信号转导通路的影响。方法通过在右无名动脉和左侧颈总动脉之间部分缩窄胸主动脉诱导大鼠心肌肥厚模型。将制好模型的大鼠随机分成6组：假手术组、胸主动脉缩窄组、胸主动脉缩窄组+低剂量丹参酮组(5mg/kg)、胸主动脉缩窄组+中剂量丹参酮组(10mg/kg)、胸主动脉缩窄组+高剂量丹参酮组(20mg/kg)、胸主动脉缩窄组+缬沙坦组(10mg/kg)。用药8周后,B超检测心肌肥厚程度和心功能的变化,将心肌样本沿横切面切开并做HE染色,Western blot法分析心肌MAPK信号蛋白表达变化。结果胸主动脉缩窄组相对于假手术组在心脏重量指数、左室重量指数、心肌纤维直径、左心室后壁及室间隔厚度均增加。而丹参酮ⅡA和缬沙坦组均可减轻上述变化的程度。Western blot结果显示：相对假手术组,模型组的p-ERK(磷酸化的细胞外信号调节激酶)和p-p38(磷酸化的p38丝裂原活化蛋白激酶)均减少,差异均具有统计学意义(均P<0.01)。相对于模型组,各丹参酮和缬沙坦治疗组p-ERK减少,差异均具有统计学意义(均P<0.05)；另外,丹参酮高剂量和中剂量组,以及缬沙坦治疗组p-p38增加,差异均具有统计学意义(均P<0.05)。结论丹参酮ⅡA通过调节MAPK通路中的蛋白表达而发挥其抑制心肌肥厚的作用。
目的研究缺血后适应对全脑缺血再灌注大鼠突触超微结构及突触素表达的影响。方法将动物随机分成3组(每组8只)：假手术组(C)、缺血再灌注组(Ⅰ)和缺血+后适应组(Post-con)。按照四血管阻塞法制作脑缺血模型：假手术组：分离动物颈总动脉,不阻断血流；缺血再灌注组：阻断双侧颈总动脉10min再灌注；缺血+后适应组：阻断双侧颈总动脉10min再灌注,于再灌注的初期给予15s灌注/15s夹闭,共三个循环的后适应。动物全脑缺血48h后断头处死,取海马组织包埋切片后,用透射电子显微镜观察海马CA1区神经元超微结构变化,并应用免疫组化和Westernblot方法观察突触素的表达。结果①电镜观察：缺血+后适应(Post-con)组与缺血再灌注(Ischemic)组相比,神经毡内突触数目较多,线粒体、突触损伤较轻。②免疫组化染色：缺血+后适应(Post-con)组与缺血再灌注(Ischemic)组相比,海马区突触素免疫活性增高,免疫产物的颗粒较大、密集、染色深；细胞排列较规则,细胞肿胀较轻。③Westernblot:缺血+后适应(Post-con)组与缺血再灌注(Ischemic)组相比,海马区突触素蛋白表达增高,三组比较差异有统计学意义(P<0.05)。结论缺血后适应可以减轻神经元的再灌注损伤,并通过调节神经元的可塑性,促进受损神经功能的恢复。
摘要现代心肺复苏技术的实施可以增加患者的自主循环恢复率并提高患者的入院率,但是患者的生存出院率却仍然不是很理想,主要原因为心跳骤停后的脑损伤。后适应现象的发现为我们打开了一扇通往内源性的神经保护之门。后适应的保护机制包括：在缺血再灌注时,减轻线粒体的钙超载和氧化应激、激活再灌注损伤救援激酶通路、预防线粒体通透性转运孔的开放。后适应的潜在临床应用优势在于能用于意外的或者是难以预测的缺血情况下的复灌。前期的实验研究显示后适应可以用于减轻突发性的冠状动脉阻塞、急性心梗以及中风后的缺血再灌注损伤。由于心跳骤停复苏时心脏和脑要面临与前述的疾病相似的病理生理过程,我们推测后适应原理同样可以用于心肺复苏的临床实践中来减轻心肺复苏后的脑损伤。我们提出了一种新的心肺复苏程序：后适应心脑复苏法。这种方法步骤为：先进行胸部按压18秒,停止按压10秒(进行通气),共3个循环。然后进行持续的胸部按压直到患者恢复自主循环。后适应心肺复苏法不仅可以为重要器官的提供血流,而且可以激活内源性的保护机制来减轻心跳骤停后的脑损伤。我们认为这个方法作为心肺复苏时脑保护的干预措施,能简单、安全、有效地预防和减轻心跳骤停后的脑损伤,改善心跳骤停的预后。
Objective To construct cardiac hypertrophy model by partially binding thoracic aorta in rats. Methods Thirty male Sprague Dawley(SD) rats were divided into sham surgery (n=10) and operation (n=20) randomly. Operation methods: The suture was snugly tied around the 22-gauge needle and the aorta which was between the origin of the right innominate and left common carotid arteries. After ligation, the needle was quickly removed. Echocardiography、the external appearance and HE staining was performed 10 weeks after the surgery. Results After 10 weeks, the volume of heart in operated rats is increased than sham-operation groups. Compared with the sham-operated, M-mode demonstrated that the operated group's left ventricle (LV) cavity and the posterior wall thickness increased markedly and its fractional shortening decreased. Compared with sham-operation groups, the operated rats showed that the interventricular septum thickness (2.527+0.269 vs.1.943+0.1, P<0.01),and the posterior wall thickness (2.492+0.242 vs.1.902+0.076, P<0.01) increased; the fractional shortening diminished(49+7.681 vs.55.7+9.828,P>0.05); the cardiac hypertrophy index increased (3.196+0.11 vs.1.785+0.099,P<0.01); the changes of LV internal diastolic dimension (LVIDd)、LV internal systolic dimension (LVIDs)and ejection fraction was not obvious. Conclusion Thoracic aorta constriction (TAC) induced rat cardiac hypertrophy will provide a reproducible model to study cardiac hypertrophy、myocardial dysfunction and myocardial remodeling.
Objective To determinate the effects of Sodium TanshinoneⅡA sulfonate (STS) on cardiomyocyte hypertrophy and explored the relative effects of STS on mitogen-activated protein kinase signal transduction system in rats with cardiomyocyte hypertrophy through constricting the thoracic aorta. Methods To make the models of cardiomyocyte hypertrophy in vivo, the thoracic aorta was partially tied between the right innominate and the left common carotid arteries. The rat randomly divided in 6 groups (n= 8/group) as follows:1) sham,2) transverse aortic constriction (TAC),3) TAC+Low-dose Tan (TAC+LT) (5mg/kg),4) TAC+ medium-dose Tan (TAC+MT) (10mg/kg),5)TAC+high-dose Tan (TAC+HT) (20mg/kg) and 6)TAC+Val (10mg/kg). After 8 week medication, Echocardiography was performed to measure the changes of hypertrophy and heart function, and heart samples were cut into transverse sections and stained with hematoxylin and eosin (H&E). The MAPKs protein expression in the cardiomyocytes was measured by western blot analysis. Results The heart weight index (HWI), left ventricular mass index (LVMI) and cross-sectional diameter of cardiomyocytes (CD), left ventricular posterior wall thickness (LVWT), interventricular septal thickness (IVS) were significantly increased than sham group as soon as 2 months post-TAC. And the relative parameters of STS groups and Val group were alleviated than the TAC group. Western blot analysis shows the p-ERK and p-p38 expression was significantly decreased in the TAC group compared with the sham group (p<0.01). The p-ERK expression was significantly decreased in the STS groups and Val group compared with the TAC group (p<0.05). The TAC+HT group, TAC+MT group and Val group had significantly higher p-p38 expression than the TAC group (p<0.05). Conclusion TanshinoneⅡA could regulate the expression of protein in MAPK pathway to exert it inhibition of hypertrophy of cardiomyocyte.
Objective:To study the effects of postconditioning on synaptic ultrastructure and synaptophysin expression in global cerebral ischemia reperfusion. Methods:To make the models of global cerebral ischemia in vivo,;the vertebral artery of rat were occluded and common their carotid arteries were transitorily cliped. The rats randomly divided in 3 groups (n= 8/group) as follows:1) control(C),2) ischemia reperfusion (I),3) ischemia+postconditioning (Post-con). Control group: beparated carotid artery and didnot blocked blood flow. Ischemia reperfusion group: bilateral carotid artery was occluded 10min then reperfusion. Ischemia+ postconditioning group:bilateral carotid artery was occluded 10min then executed postconditioning protocol (3 cycles of 15s reperfusion/15s clipping) before reperfusion. Fourty eight hours later the rat in 3 groups were killed and their brain tissues were harvested and made into slices, stained with immunohistochemical techniques, photographed under the transmission electron microscope and measured synaptophysin protein expression by western blot analysis. Results:①it was observed in the ischemia+postconditioning (Post-con) group from electric mirror that there were a relatively large number of synaptic neuropil, and the damages of mitochondria and synaptic were minor, compared with the ischemia-reperfusion (Ischemic) group,②ischemia+postconditioning (Post-con) group compared with the ischemia-reperfusion (Ischemic) group:The immunoreactivity of synaptophysin in the hippocampus increased significantly; the immune products were larger particles, dense and deeply stained; cells arranged in regular and cell swellings were less.③Western blot analysis show the synaptophysin expression was significantly increased in the Post-con group compared with the ischemic group (P<0.05). Conclusion:Postconditioning reduced reperfusion injury in neurons, regulated neuronal plasticity and promoted the recovery of nerve function.
Although current cardiopulmonary resuscitation (CPR) performance can increase the rates of restoration of spontaneous circulation (ROSC) and survival to hospital admission, the discharge rates of patients remain disappointing. The high mortality rate is attributed to post-cardiac arrest brain injury. The discovery of the postconditioning phenomenon opens a door to endogenous neuroprotection. The protection mechanisms of postconditioning include attenuating mitochondrial calcium overload and reducing oxidative stress, recruiting the reperfusion injury salvage kinase (RISK) pathway, and preventing from the mitochondrial permeability transition pore (mPTP) opening at the time of reperfusion. An advantage of postconditioning lies in the potentially clinical application in the unexpected ischemic situation. Prior laboratory researches indicate that postconditioning may lessen the reperfusion/ischemia-induced injury in unexpected coronary occlusion, acute myocardial infarction and stroke. Because cardiac arrest, stroke and acute myocardial infarction have a similar pathophysiological process, we hypothesize that postconditioning could be used in the clinical practice of CPR to treat patients with post-cardiac arrest brain injury. We propose a novel protocol of 'Postconditioning cardiocerebral resuscitation (Post-CCR)'. The Post-CCR includes applying three cycles of 18 seconds chest compression and 10 seconds interruption for ventilation first, and then executing chest compression only CPR until the patients return spontaneous circulation. Post-CCR can not only provide vital blood flow to the heart and brain but also activate endogenous protective mechanism to lessen post-cardiac arrest brain injury. We consider that it would become a feasible, safe and efficient cerebralprotective intervention in the prevention and alleviation of post-cardiac arrest brain injury, which would also improve the outcome after cardiac arrest.
引文
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