雷帕霉素在大鼠移植心脏血管病中作用的实验研究
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摘要
研究背景：移植心脏血管病(Cardiac allograft vasculopathy，CAV)是影响心脏移植病人长期存活的主要障碍。经血管内超声(Intravascular ultrasonography，IVUS)显示，心脏移植1年后，58％的病人出现血管内膜增生，移植3年后，75％的病人可发现有CAV。其特征性病理学变化为弥漫性、同心圆状的纤维性内膜增厚。由于CAV弥漫性病变的特点以及病变常常累及到远端血管，目前唯一有效的治疗方法是再次心脏移植。但由于心脏供体短缺，临床上难以实施。在对各种可能延缓CAV发生的药物研究中，虽然3-羟-3甲-戊二酰辅酶A(HMG-CoA)还原酶抑制剂、血管紧张素转换酶抑制剂或血管紧张素受体阻滞剂、抗氧化剂(VitC和VitE)、钙通道阻滞剂、肝细胞生长因子和全反式维甲酸(atRA)等药物有助于延缓CAV的发生，但作用有限。CAV的发病机制目前认为是免疫和非免疫因素共同介导的内皮激活，触发血管内膜增生及平滑肌细胞迁移和增殖的结果。预防CAV形成的最佳方法就是应用一种有抗血管内膜增生及抗平滑肌细胞迁移和增殖作用的强效免疫抑制剂。传统应用的免疫抑制剂如钙调节素抑制剂、强的松及嘌呤类生物合成抑制剂在预防CAV方面效果不明显。吗替麦考酚酯(MMF)在预防CAV的发生方面作用也有限。雷帕霉素(Rapa，又名西罗莫司)是一种强效的免疫抑制剂，同时又是一种增殖信号抑制剂，具有极好的抑制血管平滑肌细胞和新生血管内膜过度增殖的作用。大量临床研究报道雷帕霉素涂层支架在预防冠状动脉支架植入后血管再狭窄方面的效果良好。但雷帕霉素在预防和治疗CAV方面的作用如何有待进一步研究。细胞周期素依赖性激酶抑制蛋白P27kiP1是血管平滑肌细胞(VSMC)增生的重要抑制因子之一。体外实验证实雷帕霉素可通过增加P27kiP1的表达来调控细胞生长周期过程。整合素αvβ3在内皮细胞迁移过程中起着重要作用，是组织因子和细胞因子诱导平滑肌细胞增生过程中所必需的。血小板衍化生长因子(PDGF)是平滑肌细胞重要的有丝分裂原，在诱导平滑肌细胞增殖过程中起着重要作用。然而P27Kip1、整合素αvβ3 mRNA、PDGF-A mRNA在移植心脏血管组织中的表达情况及雷帕霉素对其表达有何影响尚不清楚，
Background Cardiac allograft vasculopathy(CAV) is a significant obstacle to improving outcomes in heart transplant recipients. Intravascular ultrasonography, a more sensitive technique, detects intimal thickening in up to 58% of patients at 1 year posttransplant and detects CAV in 75% of patients at 3 years. The predominant feature of CAV is a diffuse,concentric fibrous intimal hyperplasia that appears along the entire length of the affected arteries. The diffuse,obliterative nature of CAV means that changes to vascular architecture are nonreversible. Once established, the only effective treatment for the condition is retransplan-tation, but it is infrequently performed because of the limited supply of suitable organs.Because of the paucity of effective therapies for CAV, attention has been directed most toward disease prevention. Although use of 3-Hydroxy-3-methyllglutaryl coenzyme A reductase inhibitors, angio-tensin-converting enzyme inhibitors or angiotensin receptor blockers, antioxidant vitamins C and E, calcium channel blocker and all-trans retinoic acid have some effects on retarding the progression of CAV, but long-term outcomes are needed to determine whether these benefits are sustainable. Because vasculopathy is the end result of both immune- and nonimmune-mediated endothelial activation that triggers smooth muscle cell proliferation, preventing its development may best be accomplished by using an immunosuppressive drug with potent antiproliferative and antimigrative effects on vascular smooth muscle cells(VSMCs). Traditionally used immunosuppressive agents such as calcineurin inhibitors (CNIs), corticosteroids, and purine biosynthesis inhibitors have hitherto shown little efficancy for preventing CAV, mycophenolate mofetil may havs some efficacy in this regard. Nevertheless, it is clear that better treatment options for prevention of CAV are required. Rapamycin (Rapa,Sirolimus) combine effective immunosuppression with antiprolife-
Background Cardiac allograft vasculopathy(CAV) is a significant obstacle to improving outcomes in heart transplant recipients. Intravascular ultrasonography, a more sensitive technique, detects intimal thickening in up to 58% of patients at 1 year posttransplant and detects CAV in 75% of patients at 3 years. The predominant feature of CAV is a diffuse,concentric fibrous intimal hyperplasia that appears along the entire length of the affected arteries. The diffuse,obliterative nature of CAV means that changes to vascular architecture are nonreversible. Once established, the only effective treatment for the condition is retransplan-tation, but it is infrequently performed because of the limited supply of suitable organs.Because of the paucity of effective therapies for CAV, attention has been directed most toward disease prevention. Although use of 3-Hydroxy-3-methyllglutaryl coenzyme A reductase inhibitors, angio-tensin-converting enzyme inhibitors or angiotensin receptor blockers, antioxidant vitamins C and E, calcium channel blocker and all-trans retinoic acid have some effects on retarding the progression of CAV, but long-term outcomes are needed to determine whether these benefits are sustainable. Because vasculopathy is the end result of both immune- and nonimmune-mediated endothelial activation that triggers smooth muscle cell proliferation, preventing its development may best be accomplished by using an immunosuppressive drug with potent antiproliferative and antimigrative effects on vascular smooth muscle cells(VSMCs). Traditionally used immunosuppressive agents such as calcineurin inhibitors (CNIs), corticosteroids, and purine biosynthesis inhibitors have hitherto shown little efficancy for preventing CAV, mycophenolate mofetil may havs some efficacy in this regard. Nevertheless, it is clear that better treatment options for prevention of CAV are required. Rapamycin (Rapa,Sirolimus) combine effective immunosuppression with antiprolife-
引文
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