Dimmeler S, Zeiher A M
Molecular Cardiology, Department of Internal Medicine IV, University of Frankfurt, Theodor-Stern-Kai 7, 60590, Frankfurt, Germany.
Regul Pept. 2000 Jun 30;90(1-3):19-25. doi: 10.1016/s0167-0115(00)00105-1.
Reactive oxygen species (ROS) are known to induce apoptotic cell death in various cell types. In the vessel wall, ROS can be formed by macrophages within the atherosclerotic plaque or can act on the endothelium after adhesion of monocytes or leucocytes. Moreover, ROS are endogenously synthesized by endothelial and vascular smooth muscle cells by NAD(P)H oxidase. Enhanced ROS production is a very early hallmark in the atherogenic process, suggesting a link between ROS and apoptosis. In endothelial cells, the endogenous generation of ROS is induced by different pro-inflammatory and pro-atherosclerotic factors such as Ang II, oxLDL or TNFalpha, which all promote the execution of programmed cell death. ROS synthesis is thereby causally involved in apoptosis induction, because antioxidants prevent endothelial cell death. The pro-apoptotic effects of endogenous ROS in endothelial cells mechanistically seems to involve the disturbance of mitochondrial membrane permeability followed by cytochrome c release, which finally activates the executioner caspases. In contrast to the pro-apoptotic capacity of ROS in endothelial cells, in vascular smooth muscle cells emerging evidence suggests that endogenous ROS synthesis promotes cell proliferation and hypertrophy and does not affect cell survival. However, high concentrations of exogenous ROS can also stimulate smooth muscle cell apoptosis as shown for other cell types probably via activation of p53. Taken together, the double-edged effects of endogenously derived ROS in endothelial cells versus VSMC may provide a mechanistic clue to the anti-atherosclerotic effects of antioxidants shown in experimental studies, given that the promotion of endothelial survival in combination with inhibition of VSMC proliferation blocks two very important steps in the pathogenesis of atherosclerosis.
已知活性氧（ROS）可诱导多种细胞类型发生凋亡性细胞死亡。在血管壁中，ROS可由动脉粥样硬化斑块内的巨噬细胞形成，或在单核细胞或白细胞黏附后作用于内皮细胞。此外，内皮细胞和血管平滑肌细胞可通过NAD(P)H氧化酶内源性合成ROS。ROS生成增强是动脉粥样硬化形成过程中一个非常早期的标志，提示ROS与凋亡之间存在联系。在内皮细胞中，不同的促炎和促动脉粥样硬化因子如血管紧张素II（Ang II）、氧化型低密度脂蛋白（oxLDL）或肿瘤坏死因子α（TNFα）可诱导ROS的内源性生成，这些因子均促进程序性细胞死亡的执行。因此，ROS合成与凋亡诱导存在因果关系，因为抗氧化剂可防止内皮细胞死亡。内皮细胞中内源性ROS的促凋亡作用在机制上似乎涉及线粒体膜通透性的破坏，随后细胞色素c释放，最终激活执行性半胱天冬酶。与ROS在内皮细胞中的促凋亡能力相反，在血管平滑肌细胞中，新出现的证据表明内源性ROS合成促进细胞增殖和肥大，且不影响细胞存活。然而，高浓度的外源性ROS也可刺激平滑肌细胞凋亡，正如在其他细胞类型中所显示的那样，可能是通过激活p53。综上所述，内源性ROS在与血管平滑肌细胞的内皮细胞中产生的双刃剑效应，可能为实验研究中所示抗氧化剂的抗动脉粥样硬化作用提供一个机制线索，因为促进内皮细胞存活并同时抑制血管平滑肌细胞增殖可阻断动脉粥样硬化发病机制中的两个非常重要的步骤。
