Little Peter J, Ivey Melanie E, Osman Narin
Cell Biology of Diabetes Laboratory, Division of Vascular Biology, Baker Heart Research Institute, Melbourne, Victoria, Australia.
Curr Vasc Pharmacol. 2008 Jul;6(3):195-203. doi: 10.2174/157016108784911966.
The formation and progression of atherosclerotic plaques followed by rupture, thrombus formation and vessel blockage leads to ischemic tissue damage and the clinical condition underlying most cardiovascular disease. Therapeutic agents for the prevention of atherosclerosis have all targeted epidemiologically-identified and relatively easily measured risk factors (e.g. lipids and blood pressure). This strategy has proven somewhat effective but is of less than optimal efficacy as rates of cardiovascular disease remain high. Treatment targeting the mechanisms of atherosclerosis in the vessel wall is a conceptually attractive proposition to complement the risk factor directed strategy. Vascular smooth muscle cells (VSMC) are the major cellular component of the vascular media and migration and proliferation leads to the formation of the neointima the development of which renders the vessels particularly sensitive to atherosclerosis. Numerous hormones and growth factors act on VSMC to cause migration, proliferation and the secretion of extracellular matrix and modulation or dysfunction of these processes is the most likely cause of atherosclerosis. Endothelin-1 (ET-1) is a 21 amino acid peptide that acts on 7 transmembrane G protein coupled receptors to elicit a plethora of responses that can modulate the behaviour of VSMCs and thus impact on the development of atherosclerosis. ET-1 is elevated in atherosclerotic plaques. People with diabetes have accelerated atherosclerosis and also show elevated plasma levels of ET-1. This review addresses the actions of ET-1 on VSMC and the signalling pathways through which it mediates its effects as the latter represent potential therapeutic targets for the prevention of atherosclerosis.
动脉粥样硬化斑块的形成、进展，随后破裂、血栓形成和血管阻塞，会导致缺血性组织损伤以及大多数心血管疾病的临床状况。预防动脉粥样硬化的治疗药物都针对流行病学确定且相对易于测量的危险因素（如血脂和血压）。这一策略已被证明有一定效果，但由于心血管疾病的发病率仍然很高，其疗效并不理想。针对血管壁动脉粥样硬化机制的治疗是一种在概念上有吸引力的提议，可作为针对危险因素策略的补充。血管平滑肌细胞（VSMC）是血管中层的主要细胞成分，其迁移和增殖会导致新内膜的形成，新内膜的发展使血管对动脉粥样硬化特别敏感。许多激素和生长因子作用于VSMC，导致其迁移、增殖以及细胞外基质的分泌，这些过程的调节或功能障碍很可能是动脉粥样硬化的原因。内皮素-1（ET-1）是一种由21个氨基酸组成的肽，它作用于7次跨膜G蛋白偶联受体，引发大量反应，这些反应可调节VSMC的行为，从而影响动脉粥样硬化的发展。ET-1在动脉粥样硬化斑块中升高。糖尿病患者的动脉粥样硬化进展加速，血浆ET-1水平也升高。本综述探讨了ET-1对VSMC的作用及其介导作用的信号通路，因为后者是预防动脉粥样硬化的潜在治疗靶点。
