摘要
动脉粥样硬化性血栓形成的病理基础是动脉粥样斑块破裂与继发血栓形成。传统的观点认为动脉粥样硬化血栓形成与吸烟、缺乏运动、不合理饮食，以及高血压、血脂异常、糖尿病、肥胖、代谢综合征等危险因素密切相关。近来研究显示男性随着年龄的增加睾酮水平下降。血睾酮水平降低与男性冠心病、主动脉或颈动脉粥样硬化危险性增加有关。雄激素受体在冠状动脉粥样硬化形成早期具有重要作用，雄激素受体表达与动脉粥样硬化严重程度密切相关。Alevizaki M等报告男性冠状动脉粥样硬化与雄激素受体基因CAG重复多态性密切相关。Zitzmann M等报告雄激素受体基因CAG重复率低与HDL-C水平降低密切相关。我们课题组以往的研究认为雄激素水平与冠心病、下肢动脉闭塞症显著负相关。但是以往研究的结果并不能说明低雄激素血症是冠心病的结果抑或是其原因；雄激素对动脉粥样硬化作用尚有争议；雄激素、雄激素受体在动脉粥样硬化斑块稳定性中的作用尚不清楚，相关机制尚未完全阐明。
流行病学研究显示，男性血栓性心血管疾病显著高于女性。伴有低雄激素血症的老年男性血栓性疾病的发病率较高。动脉粥样硬化斑块破裂后继发血栓形成是动脉粥样硬化性血栓形成的重要病理过程，目前雄激素与其受体在动脉血栓形成中的作用尚不完全清楚，其机制也有待进一步研究。本课题的研究目的是探讨雄激素与其受体在动脉粥样硬化进展、斑块稳定性和血栓形成的作用与机制，进而为低雄激素血症老年男性进行动脉粥样硬化性血栓形成的一级预防与临床干预提供依据。
第一部分：睾酮及氟他胺对雄免动脉粥样硬化进展、斑块稳定性的作用与机制研究
目的：老年男性随着年龄的增加睾酮水平下降。与同年龄健康男性比较，男性冠心病患者的生物有效性睾酮较低。血睾酮水平降低与主动脉或颈动脉粥样硬化危险性增加有关。睾酮替代治疗可明显抑制去睾丸雄性动物动脉粥样硬化的进展。然而，雄激素与其受体在动脉粥样硬化斑块稳定性中的作用尚不清楚，作用机制亦有待进一步阐明。本研究拟探讨睾酮及其受体对动脉粥样硬化斑块的病变进展与稳定性的调节作用，并进一步观测睾酮及其受体对血浆炎症因子的调节，以阐明雄激素对动脉粥样硬化斑块稳定性调节的可能机制。
方法：高脂饲料喂养成熟雄性新西兰白兔，制备动脉粥样硬化模型。腹主动脉病理切片行苏木精-伊红(HE)染色和Masson氏三色染色观察动脉粥样硬化斑块的病理改变与斑块面积、纤维帽厚度、胶原含量变化。血浆睾酮(T)应用Advia Centaur免疫检测系统测定(Bayer，Germany)采用化学发光免疫分析法测定。血浆二氢睾酮(DHT)应用酶联免疫试剂盒(ELISA kit)推荐方法检测。血清肿瘤坏死因子(TNFα)和白细胞介素6(IL_6)采用放射免疫测定，血清可溶性细胞间粘附分子-1(sICAM-1)和MMP_2)应用酶联免疫吸附测定法(ELISA)检测。血浆睾酮采用Advia Centaur免疫检测系统(Bayer，Germany)，应用化学发光免疫分析法检测。血浆内皮素-1、血浆肾素活性、血管紧张素Ⅱ水平，根据放射免疫试剂盒推荐步骤应用放射免疫法检测。
结果：雄兔去睾丸血浆睾酮水平显著降低，补充十一酸睾酮(6mg/kg／2w)使血浆睾酮恢复到水平，而且十一酸睾酮这一作用不受雄激素受体拮抗剂(氟他胺)的影响。去睾丸雄兔补充十一酸睾酮显著减低动脉粥样斑块的面积、内膜厚度，并使斑块纤维帽增厚、胶原含量增加。然而，同时补充氟他胺使去睾丸雄兔动脉粥样斑块的面积显著、内膜厚度增加，并使斑块纤维帽厚度减低、胶原含量下降。与假手术高脂喂养雄兔比较，去睾丸雄兔血清TNFα、IL_6、sICAM-1和MMP_2显著升高；去睾丸雄兔补充十一酸睾酮后，血清TNFα、IL_6、sICAM-1和MMP2较单纯去睾丸雄兔明显降低；去睾丸雄兔同时补充氟他胺(雄激素受体拮抗剂)与十一酸睾酮，血清TNFα、IL_6、sICAM-1和MMP_2水平再次显著升高。与标准饲料喂养雄兔比较，高脂喂养雄兔血浆ET-1、PRA、AngⅡ水平显著增加。在高脂喂养雄兔中，去睾丸-睾酮组、去睾丸-睾酮-Flut组的血浆ET-1、PRA、AngⅡ水平与假手术组无明显差异。
结论：雄激素与其受体调节雄兔动脉粥样硬化斑块进展与斑块的稳定性，这种作用与其影响血清炎症反应有关。
第二部分：雄激素对三氯化铁诱导雄性大鼠动脉血栓形成的作用与机制研究
目的：心、脑和周围血管疾病存在一个共同病理改变，即动脉粥样硬化血栓形成(atherothrombosis)。冠状动脉内血栓形成是急性冠脉综合征(ACS)与冠脉介入引起的缺血并发症的关键事件。抗血栓的策略在治疗与防治动脉粥样硬化血栓症具有重要地位。近年来，男性低雄激素水平在ACS中的作用受到了越来越多的关注。老年男性睾酮水平随着年龄的升高而逐渐下降，但是心血管疾病的发生率却明显增加。男性性激素在动脉粥样硬化性血栓形成的作用尚不完全清楚，其机制也有待遇进一步阐明。本研究的目的是探讨生理剂量雄激素是否通过其受体调节实验性动脉血栓形成，并进一步阐述相关机制。
方法：三氯化铁(FeCl_3)作为刺激因子诱发的实验性大鼠腹主动脉血栓形成模型。应用血小板聚集仪测定血小板聚集、血小板粘附仪测定血小板粘附。应用流式细胞仪测定血小板内钙离子浓度。应用放射免疫分析法测定TXB_2和6-Keto-PGF_(1α)。凝血与纤溶参数采用STA-R血凝分析仪检测；血浆粘度应用SA-6000自动血液流变学检测仪测定。
结果：雄性大鼠去睾丸后血浆睾酮与二氢睾酮明显降低(7．94±3．07nmol／L比0．96±0．09nmol／L；1．76±0．77nmol／L比0．1±0．02nmol／L，P均<0．05)。去睾丸雄性大鼠每日补充DHT(0．25 mg/rat)使其DHT浓度达到生理水平，而且与氟他胺(flutamide)(每两日注射一次5mg／rat)联用不影响DHT浓度达到生理水平。去睾丸大鼠FeCl_3刺激诱发的主动脉血栓的面积和重量显著高于假手术大鼠。自体贫血小板血浆(PPP)稀释富血小板血浆(PRP)后，1μM二磷酸腺苷(ADP)诱导的血小板的聚集率为9．10％；Tyrode氏缓冲液稀释PRP后，1μM ADP诱导的血小板的聚集率为63．65％。Tyrode氏缓冲液稀释PRP后，如果应用DHT(1nM，2nM)预处理PRP，1μM ADP诱导的血小板的聚集率再次降低。而且自体PPP稀释PRP后，去睾丸大鼠血小板聚集明显高于假手术大鼠，去睾丸大鼠PRP补充DHT(2nM)后，血小板聚集率下降到与假手术组相似的水平。在自体PPP或Tyrode氏缓冲液稀释的PRP，氟他胺(3μM)预处理后，1μM ADP诱导的血小板的聚集率再次增加。Tyrode氏缓冲液稀释PRP后，DHT(2nM)预处理显著降低1μM ADP诱发的血小板粘附，但是如果氟他胺(3μM)预处理后，1μM ADP诱发的血小板粘附再次增加。
去睾丸大鼠生理剂量DHT补充治疗明显降低TXB_2与6-keto-PGF_(1α)的比率，然而氟他胺与DHT联合补充治疗则显著增加TXB_2与6-keto-PGF_(1α)的比率。DHT(2nM)明显降低ADP诱导的血小板内钙离子浓度。然而，氟他胺预处理血小板之后ADP诱导的血小板内钙离子浓度再次增加。去睾丸大鼠血浆凝血酶原活动度(PA％)显著升高(68．00±4．74比53．00±1．81，P<0．05)，而凝血酶原时间(PT)、活化的部分凝血酶时间(APTT)、国际标准化比值(INR)显著降低(P均<0．05)。去睾丸大鼠血浆纤维蛋白原(FIB)、纤溶酶原活性(PLG：A)、D-二聚体(D-dimer)、血浆粘度与假手术大鼠间无差别(P均>0．05)。
结论：雄激素与其受体通过调节血小板激活以及凝血系统，进而部分抑制雄性大鼠实验性动脉血栓形成。
第三部分：雄激素和其受体介导调节血栓素A_2释放影响氧化应激诱发的血小板聚集的研究
目的：血小板功能与血栓形成密切相关，尤其是动脉血栓形成。大多数动脉血栓形成始于血管内皮损伤。血小板激活调节异常是动脉血栓形成的重要原因之一。氧化应激因其损伤血管内皮功能、促进血小板聚集，因而在急性冠脉综合征发病中起着重要作用。本研究的目的是探讨生理剂量雄激素和其受体在氧化应激诱发的血小板聚集中的作用，并进一步研究相关机制。
方法：血浆(Dihydrotestosterone，DHT)应用酶联免疫试剂盒(ELISA kit)推荐方法检测。应用血小板聚集仪采用透射比浊法测定血小板聚集。应用放射免疫试剂盒采用放免法测定血栓素B_2(TXB_2)。
结果：应用Tyrode氏缓冲液稀释PRP后，补充DHT(2nM)显著抑制过氧化氢(H_2O_2)(10mM，25mM)诱导的血小板聚集。应用自体PPP稀释PRP后，假手术大鼠H_2O_2诱发的血小板聚集明显下降；而去睾丸大鼠H_2O_2诱发的血小板聚集则明显增加；去睾丸大鼠PRP补充DHT(2nM)后，H_2O_2诱发的血小板聚集显著下降；去睾丸大鼠PRP补充氟他胺(3μM)与DHT(2nM)后，H_2O_2诱发的血小板聚集再次明显增加。应用DHT(2nM)预处理去睾丸大鼠PRP，H_2O_2诱发的血小板释放血栓素A_2(TXA_2)明显减低；而应用氟他胺(3μM)与DHT(2nM)联合预处理去睾丸大鼠PRP，H_2O_2诱发的血小板释放血栓素A_2(TXA_2)则明显增加。去睾丸大鼠血浆睾酮与DHT水平显著下降。去睾丸大鼠每日注射DHT(0．25mg／rat)后，血浆DHT又恢复至生理水平；若去睾丸大鼠补充DHT同时，每两日注射一次氟他胺((5mg／rat)，血浆DHT仍然处于生理水平。去睾丸大鼠血浆TXB_2较假手术大鼠显著增加。去睾丸大鼠每日注射DHT(0．25mg/rat)后，血浆TXB_2再次下降；若去睾丸大鼠补充DHT同时，每两日注射一次氟他胺((5mg／rat)，血浆TXB_2再次显著增加。
结论：生理剂量雄激素介导其受体抑制氧化应激诱发的血小板聚集，这种作用与其减少血小板TXA_2释放有关。
The basic pathology of atherothrombosis is atherosclerotic plaque rupture and sequential thrombus formation. Traditionally, it is believed that atherothrombosis is closely related with such factors as smoking, lackness of exercise, irrational diet, hypertension, lipid disorder, diabetes, obesity and metabolism syndrome. Recent studies demonstrate that the levels of testosterone decrease with the increase of age, which is related to the risk increase of male coronary heart disease, aortic or carotid atherosclerosis. Androgen receptor palys an important role in the early phase of atherosclerosis formation and the decrease of its expression is associated with the severity of atherosclerosis progress. The study of Alevizaki, et al. revealed that the androgen receptor gene CAG polymorphism is associated with the severity of coronary artery disease in men. The study of Zitzmann, et al. demonstrated that shorter, more androgenic AR alleles with fewer CAG repeats are associated with lower HDL-C.
The previous studies of our group disclosed that the level of androgen is negatively related to coronary heart disease and peripheral arterial disease. However, these studies didn't suggested that low leve of androgen is a result or cause of coronary heart disease. It is conflicting view which roles androgen plays in atherosclerosis progress. Atherosclerotic plaque rupture is an early phase in the atherothrombosis formation. Presently, it is unclear whether androgen and its receptor play roles in plaque stability, which the mechanisms corncerned still were elucidated. Acute thrombus formation is an important pathological progress of atherothrombosis.
Epidemiological studies demonstrated that the morbidity of cardivascular disease is higher in men than in women. The older the male is, the higher is the morbidity of atherothrombosis. These studies reveal that androgen maybe plays an important role in atherothrombosis formation. However, it is unclear whether androgen and its receptor play roles in thrombus formation, which the mechanisms corncerned still need to be studied further.
The purposes of the study are to determine the influence of androgen and its receptor on atherosclerotic plaque growth, stability and arterial thrombosis,to investigate the mechanisms concerned, and to further provide interventional target and evidence for first-level prevention of atherothrombosis in the eldly male with low level of androgen.
PartⅠ: Regulation and mechanisms corncerned of Atherosclerotic Progress and Plaque Stability by Testosterone and Flutamide in Male Rabbits
Objectives: The purposes of the study are to determine the influence of androgen and its receptor on atherosclerotic plaque growth, stability and arterial thrombosis and further to investigate the mechanisms concerned.
Methods: Pathological sections of aorta were performed hematoxylin-eosin staining and Masson's trichrome staining. Total plasma testosterone was measured using ADVIA Centaur(?) Immunoassay System (Bayer, Germany), whereas DHT levels were measured using a DHT ELISA kit. The contents of serum tumor necrosis factor-α(TNFα) and interleukin-6 (IL_6) were assayed using radio-immunoassay kit. The concentrations of serum soluble intercellular adhesion molecule-1 (sICAM-1) and matrix metallopeptidase 2(MMP_2) were assayed using ELISA kit according to the procedure described by the manufacturer. The contents of plasma endothelin-1, plasma renin activity and angiontensinⅡwere assayed using radio-immunoassay kit.
Results: Our results showed that testosterone undecanoate replacement reduced the plaque area, the aortic intimal thickness and increased the fibrous cap thickness and collagen contents in castrated rabbits. However, presence of flutamide increased the plaque area, the aortic intimal thickness and decreased the fibrous cap thickness and collagen contents in castrated rabbits again. Our results still revealed that levels of serum TNF_α, IL_6, sICAM and MMP_2 increased in cholesterol-rich diet rabbits as compared with standard diet rabbits. Castration caused an increase in levels of serum TNF_α, IL_6, sICAM and MMP_2 in castrated rabbits as compared with sham-operated rabbits. Treatment of testosterone undecanoate reduced the levels of serum TNF_α, IL_6, sICAM and MMP_2 in castrated rabbits. However, presence of flutamide increased the levels of serum TNF_α, IL_6, sICAM and MMP_2 again. In our study, we didn't find that testosterone undecanoate replacement or treatment with flutamide affected the levels of plasma endothelin-1, plasma renin activity and angiontensinⅡin castrated rabbits as compared with sham-operated rabbits.
Conclusion: Androgen and its receptor can regulate atherosclerotic plaque growth and stability, which is related to influence inflammatory reaction in male rabbits;
ParetⅡ: Roles and Mechanisms of Androgen in ferric-chloride-induced Arterial Thrombosis in Rats
Objectives: The aim of our study is to elucidate roles androgen and its receptor in ferric-chloride-induced arterial thrombosis and mechanisms corncerned in rats
Methods: Castrated models and experimental thrombosis models of male rats were prepared. Platelet aggregometer was used to measure platelet aggregation, and platelet adherometer was used to measure platelet adhesion. The contents of TXB_2 and 6-Keto-PGF_(1α)awere assayed using radio-immunoassay kit. The intraplatelet free calcium concentrations were measured with Fluo-3/AM FCM assay. Parameters of blood coagulation and fibrinolytic system were assayed using STA-R Coagulation analyzers, and Plasma viscosity was tested using SA-6000 automated hemorrheology tester.
Results: DHT replacement restored circulating DHT to physiological levels, without being altered by treatment with flutamide. Pretreatment with DHT (2nM) significantly inhibited the platelet aggregation and adhesion induced by ADP. After PRP was pretreated with flutamide, ADP-induced platelet aggregation and adhesion increased again. After castration and DHT replacement, the ratio of both TXB2 and 6-keto-PGF_(1α) obviously decreased. However, administration of flutamide to DHT treated castrated rats caused an increase in the proportions of both TXB_2 and 6-keto-PGFia again. DHT (2nM) replacement obviously reduced [Ca~(2+)]_i,. However, Pretreatment with flutamide and DHT (2nM), [Ca~(2+)]_i increase induced by ADP was observed once more.
Castration caused a significant reduction in plasma testosterone and DHT levels, whereas DHT replaced at a dose of 0.25mg/rat restored circulating DHT to physiological levels, without being altered by treatment with flutamide. The plasma TXB2 increased in castrated rats as compared with that in sham-operated rats. Replacement of DHT reduced plasma TXB2 contents in castrated rats. However, flutamide supplementation increased plasma contents of TXB2 in castrated rats again. In addition, total plasma testosterone and DHT were significantly lower in castrated rats than in normal rats (7.94±3.07nmol/L vs 0.96±0.09nmol/L; 1.76±0.77nmol/L vs 0.1±0.02nmol/L, (all P<0.05). Castration caused significant increase in the thrombus area and weight in castrated rats as compared with control group (1157.38±68.74μm~2 vs 969.43±22.66μm~2; 7.17±1.72 mg vs 5.17±1.17 mg, all P<0.05). DHT replacement restored circulating DHT to physiological levels, without being altered by treatment with flutamide. Pretreatment with DHT (2nM) significantly inhibited the platelet aggregation and adhesion induced by ADP. After PRP was pretreated with flutamide, ADP-induced platelet aggregation and adhesion increased again. After castration and DHT replacement, the ratio of both TXB2 and 6-keto-PGF_(1α) obviously decreased. However, administration of flutamide to DHT treated castrated rats caused an increase in the proportions of both TXB2 and 6-keto-PGF_(1α) again. DHT (2nM) replacement obviously reduced [Ca~(2+)]_i,. However, Pretreatment with flutamide and DHT (2nM), [Ca~(2+)]_i increase induced by ADP was observed once more. Prothrombin activity (PA%) was higher, and prothrombin time (PT), activated partial thromboplastin time (APTT) and international normalized ratio (INR) were lower in castrated rats than in normal rats (all P<0.05). There weren't significant difference in FIB, D-dimer and plasma between in castrated rats and in normal rats (all P>0.05).
Conclusion: Androgen and its receptor regulate experimental arterial thrombosis via modulating platelet activation and coagulation processes in male rats;
PartⅢ: Inhibition of oxidative-stress-induced platelet aggregation by androgen at physiological levels via its receptor is associated with the reduction of thromboxane A_2 release from platelets
Objectives: Platelets play a crucial role in the development of arterial thrombosis and other pathophysiologies leading to clinical ischemic events. Defective regulation of platelet activation/aggregation is a predominant cause for arterial thrombosis. The purposes of our study are to assess the effect of physiological concentration of androgen via its receptor on oxidative-stress-induced platelet aggregation and to further elaborate the active mechanism.
Methods: Dihydrotestosterone (DHT) was determined by ELISA using a commercially available kit. Platelet aggregometer was used to measure platelet aggregation. The contents of thromboxane B_2(TXB_2) were assayed using radio-immunoassay kit.
Results: Our results showed that addition of DHT (2nM) significantly inhibited platelet aggregation induced by hydrogen peroxide (H_2O_2)(10mM, 25mM) in PRP diluted with Tyrode's buffer. Moreover, H_2O_2-induced platelet aggregation decreased in sham-operated rats. However, H_2O_2-induced platelet aggregation significantly increased in castrated rats. Replacement of DHT inhibited H_2O_2-induced platelet aggregation in castrated rats. After PRP was pretreated by flutamide, H_2O_2-induced platelet aggregation increased in castrated rats again. Presence of DHT (2nM) obviously inhibited H_2O_2-induced thromboxane A_2 (TXA_2) release in castrated rats. Pretreatment of DHT and flutamide increased H_2O_2-stimulated TXA_2 release from platelet in castrated rats again. Castration caused a significant reduction in plasma testosterone and DHT levels, whereas DHT replaced at a dose of 0.25mg/rat restored circulating DHT to physiological levels, without being altered by treatment with flutamide. The plasma TXB_2 increased in castrated rats as compared with that in sham-operated rats. Replacement of DHT reduced plasma TXB_2 contents in castrated rats. However, flutamide supplementation increased plasma contents of TXB_2 in castrated rats again.
Conclusion: Androgen at physiological doses via its receptor inhibits oxidative-stress-induced platelet aggregation, which is associated with the reduction of TXA_2 release from platelets.
引文
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