Fas expression and the progression of atherosclerosis-A possible participation

最近的证据表明，易损斑块破裂伴血栓形成是心血管事件发生的关键触发因素。在许多动脉粥样硬化病变的选定细胞区域内，血管细胞中存在显著的凋亡，并且这几乎可以在没有细胞增殖的情况下发生。然而，目前尚不清楚凋亡过程如何参与动脉粥样硬化斑块破裂的发生，本项目首先利用流式细胞仪，我们发现氧化应激H_2O_2可诱导内皮细胞Fas表达上调，蛋白酪氨酸激酶的激活可能参与了H_2O_2诱导Fas表达的机制。虽然细胞对一氧化氮（NO）细胞毒性作用的防御机制尚不清楚，我们还发现从血管平滑肌细胞（VSMCs）释放的血管内皮生长因子（VEGF）在p53介导的途径下游保护EC免受NO诱导的凋亡。因此，血管平滑肌细胞缺乏的斑块中的内皮细胞可能更容易受到NO诱导的细胞毒性的影响，我们现在试图用动物模型来研究这些可能性。

Recent evidence has shown that rupture of vulnerable plaque with thrombosis is a critical trigger for the development of cardiovascular events.Within selected, cellular regions of many of the atherosclerotic lesions, marked apoptosis is present in vascular cells and that this can occur virtually in the absence of cellular proliferation.However, it is not clear how apoptotic process participate in the genesis of plaque rupture in the atherosclerotic lesions.In this project we first focused on the regulatory mechanism of apoptosis in the vascular cells using a cell culture system.We found that oxidative stress H2O2 induces up-regulation of Fas in endothelial cells (ECs) and that activation of protein tyrosine kinase may be involved in the mechanism of H2O2-induced Fas expression.Although cellular defense mechanisms against the cytotoxic actions of nitric oxide (NO) in the arterial wall are not clear, we also found that vascular endothelial growth factor (VEGF) released from vascular smooth muscle cells (VSMCs) protect ECs from NO-induced apoptosis at down-stream of p53-mediated pathway.Thus, ECs in the VSMC-poor plaques may be more susceptible to NO-induced cytotoxicity.We are now trying to investigate these possibilities using animal models.