Pluripotential mechanisms of cardioprotection with HMG-CoA reductase inhibitor therapy.
Pluripotential mechanisms of cardioprotection with HMG-CoA reductase inhibitor therapy.
复制标题
DOI：
10.2165/00129784-200101060-00001
复制
发表时间：
2001-01-01
期刊：
影响因子：
--
通讯作者：
Rosenson, R S
中科院分区：
文献类型：
--
作者：
Rosenson, R S
使用羟甲基戊二酰辅酶A（HMG-CoA）还原酶抑制剂治疗可降低心血管事件的风险。临床获益的快速起效和血浆低密度脂蛋白胆固醇水平与冠状动脉管腔变化或心血管事件之间的弱相关性表明，HMG-CoA还原酶抑制剂的这种有益作用涉及非脂质机制。此外，与稳定型冠心病患者相比，急性冠状动脉综合征或急性心肌梗死患者中HMG-CoA还原酶抑制剂的临床获益起效更快，表明HMG-CoA还原酶抑制剂促进破裂或溃疡性动脉粥样硬化斑块的修复，促进斑块稳定和/或减少破裂斑块上的血栓形成。用HMG-CoA还原酶抑制剂治疗可改善高胆固醇血症患者的内皮功能障碍，这种内皮功能的改善与血清总胆固醇水平的降低无关。同样，内皮前内皮素原mRNA表达和内皮素合成的减少以及HMG-CoA还原酶抑制剂的降压作用与降脂作用无关。最后，HMG-CoA还原酶抑制剂增加了内皮一氧化氮水平，即通过转录后机制上调内皮一氧化氮合成酶表达，并阻止氧化LDL-C下调。已显示HMG-CoA还原酶抑制剂通过抑制免疫活性细胞（如巨噬细胞）的活化和T细胞向巨噬细胞的抗原呈递来调节免疫应答。HMG-CoA还原酶抑制剂治疗可降低趋化因子（单核细胞趋化蛋白-1）和促炎细胞因子[肿瘤坏死因子α、白细胞介素（IL）-6和IL-1 β]的表达、产生和循环水平。HMG-CoA还原酶抑制剂减少了人类动脉粥样硬化的炎症：巨噬细胞和T细胞显著减少，氧化LDL-C减少，胶原蛋白含量增加。此外，用HMG-CoA还原酶抑制剂治疗导致动脉粥样硬化内细胞死亡减少。用这些药物治疗还减少诱导型细胞粘附分子的表达，减少巨噬细胞分泌金属蛋白酶，减少血管平滑肌细胞凋亡。最后，HMG-CoA还原酶抑制剂似乎对血栓形成具有重要影响：组织因子产生和活性的表达降低;组织因子包抑制剂的产生增加;降低血小板血栓形成并由于降低纤溶酶原激活物抑制剂-1水平而改善纤维蛋白溶解。随着HMG-CoA还原酶抑制剂的多能性心脏保护机制的进一步阐明，可以设想在高胆固醇血症患者中更早和更频繁地开始HMG-CoA还原酶抑制剂治疗。
Treatment with hydroxymethylglutaryl coenzyme A (HMG-CoA) reductase inhibitors has been accompanied by a reduced risk of cardiovascular events. Rapid onset of clinical benefit and weak correlations between plasma low density lipoprotein-cholesterol levels and coronary lumen change or cardiovascular events indicates that nonlipid mechanisms are involved in this beneficial effects with HMG-CoA reductase inhibitors. Furthermore, more rapid onset of clinical benefit with HMG-CoA reductase inhibitors in patients with acute coronary syndromes or acute myocardial infarction than in those with stable coronary heart disease suggest that HMG-CoA reductase inhibitors facilitate repair of ruptured or ulcerated atherosclerotic plaque, facilitate plaque stabilization and/or reduce thrombus formation on ruptured plaques. Treatment with HMG-CoA reductase inhibitors improved endothelial dysfunction in patients with hypercholesterolemia and this improvement in endothelial function was not correlated with reduction in total serum cholesterol levels. Similarly, reduction in endothelial pre-proendothelin mRNA expression and endothelin synthesis and blood pressure lowering with HMG-CoA reductase inhibitors occurred independent of lipid-lowering. Finally, HMG-CoA reductase inhibitors increased endothelial nitric oxide levels i.e. upregulated endothelial nitric oxide synthetase expression via post-transcriptional mechanisms and prevented its down-regulation by oxidized LDL-C. HMG-CoA reductase inhibitors have been shown to modulate the immune response by inhibiting activation of immune-competent cells such as macrophages, and antigen presentation to macrophages by T cells. Treatment with HMG-CoA reductase inhibitors can reduce expression, production and circulating levels of chemokines (monocyte chemoattractant protein-1) and proinflammatory cytokines [tumor necrosis factoralpha, interleukin (IL)-6 and IL-1beta]. HMG-CoA reductase inhibitors reduced inflammation in human atheroma: significantly fewer macrophages and T cells, less oxidized LDL-C and higher collagen content. In addition, treatment with HMG-CoA reductase inhibitor led to decreased cell death within the atheroma. Treatment with these agents also reduced expression of inducible cellular adhesion molecules, decreased secretion of metalloproteinases by macrophages, reduced vascular smooth muscle cell apoptosis. Lastly, HMG-CoA reductase inhibitors appear to have important effects on the thrombogenesis: reduced expression of tissue factor production and activity; increased production of tissue factor package inhibitor; decreased platelet thrombus formation and improved fibrinolysis as a result of lowered plasminogen activator inhibitor-1 levels. As the pluripotential cardioprotective mechanisms of HMG-CoA reductase inhibitors are further elucidated, it is envisaged that treatment with HMG-CoA reductase inhibitors will be initiated earlier and more frequently in patients with hypercholesterolemia.