POTENTIAL ROLES OF COMPLEMENT IN ATHEROGENESIS

内皮损伤被认为是启动 动脉粥样硬化病变；随后，脂质堆积，巨噬细胞 平滑肌细胞的募集、内膜增殖与纤维化 可能发生；最终血栓形成可能导致血管闭塞。这个 末端补体蛋白C5b-9已在 人的动脉粥样硬化斑块和病变前的内皮细胞 动脉粥样硬化高胆固醇血症动物模型的研究进展。 证据还表明，补体在加速的 在人类同种异体心脏移植中观察到动脉粥样硬化。我们之前的工作 已证明补体可诱导促凝血反应 和初步数据表明，血管内皮细胞的沉积 C5b-9蛋白改变内皮细胞-脂蛋白界面和 内皮细胞表面对纤溶的调节。这项研究建议 探讨补体激活可能通过这两种机制 促进动脉粥样硬化的进展。具体目标是：1) 确定补体是否影响内皮细胞结合或 低密度脂蛋白或乙酰化低密度脂蛋白的代谢，或改变内皮细胞的通透性 对这些脂蛋白；2)确定其升高的机制 观察到高密度脂蛋白(及其载脂蛋白)与C5b-9的结合，以及 评价高密度脂蛋白/载脂蛋白结合改变对血管内皮细胞功能的影响 内皮细胞胆固醇动态平衡；3)确定 补体改变脂蛋白(A)的结合或代谢；以及4) 补体诱导的纤溶酶原结合部位的特征 内皮细胞，并确定纤溶酶原激活是否 促进或损害这些细胞。定义补体诱导 血管内皮脂代谢和纤溶系统的改变 了解补体如何调节疾病进展的基础 动脉硬化。

Endothelial injury is believed to be a requirement for the initiation of atherosclerotic lesions; subsequently, lipid accumulation, macrophage recruitment, intimal proliferation of smooth muscle cells, and fibrosis may occur; ultimately thrombosis may result in vessel occlusion. The terminal complement proteins C5b-9 have been demonstrated in atherosclerotic plaques in man, and in endothelium prior to lesion development in a hypercholesterolemic animal model of atherosclerosis. Evidence also suggests that complement plays a role in the accelerated atherosclerosis observed in human cardiac allografts. our previous work has demonstrated that complement induces procoagulant responses from endothelial cells, and preliminary data suggests that deposition of the C5b-9 proteins alters both the endothelial-lipoprotein interface and endothelial surface regulation of fibrinolysis. This research proposal explores these two mechanisms by which complement activation may contribute to progression of atherosclerosis. Specific aims are: 1) to determine whether complement effects the endothelial binding or metabolism of LDL or acetylated LDL, or alters endothelial permeability to these lipoproteins; 2) to determine the mechanism of the increased binding of HDL (and its apoproteins) observed in response to C5b-9, and to evaluate functional effects of altered HDL/apoprotein binding on endothelial cell cholesterol homeostasis; 3) to determine whether complement alters binding or metabolism of lipoprotein(a) ; and 4) to characterize the complement-induced plasminogen binding sites on endothelial cells, and determine whether plasminogen activation is facilitated or impaired on these cells. Defining complement-induced alterations in endothelial lipid metabolism and fibrinolysis is fundamental to understanding how complement may modulate progression of atherosclerosis.