基于高密度脂蛋白代谢与重塑的抗动脉粥样硬化研究及相关药物

Anti-atherosclerosis Related Drugs Based on High-Density Lipoprotein Metabolism and Remodeling Process

动脉粥样硬化(atherosclerosis,AS)是一种主要因血脂代谢紊乱引发的慢性炎症性血管疾病,以血管内膜下巨噬细胞和血管平滑肌细胞过度蓄脂泡沫化为主要病理特征。高密度脂蛋白(high-density lipoprotein,HDL)通过胆固醇逆向转运(reverse cholesterol transport,RCT)将外周细胞中的胆固醇运输到肝脏然后经胆汁排出体外,从而改善血脂水平和细胞的过度蓄脂,被认为是HDL抗AS的基础。然而,大量流行病学证据表明,虽然血浆高密度脂蛋白胆固醇(high-density lipoprotein cholesterol,HDL-C)水平与心血管风险呈负相关,但仅仅提高HDL-C水平的治疗策略不一定能增加临床效益。因此,学术界认识到HDL水平不足以反映其RCT能力,而更多取决于HDL功能。本文综述了参与调节HDL功能的各种分子对HDL代谢与重塑过程的影响,以及针对上述过程的相关药物研究进展,为更全面评价HDL的抗AS作用提供理论参考。

Atherosclerosis(AS),the pathological basis of most cardiovascular diseases,is a chronic inflammatory vascular disease with disorders of lipid metabolism.It is characterized by excessive lipid accumulation and foaming of macrophages and smooth muscle cells in the intima of blood vessels,which triggers atherosclerotic plaque development and subsequent thrombus formation.High-density lipoprotein(HDL)is a class of cholesterol-rich lipoprotein particles that transport cholesterol from peripheral cells to the liver for biliary excretion via reverse cholesterol transport(RCT),which is thought to be the basis of HDL’s anti-atherogenic properties.The inverse association between high-density lipoprotein-cholesterol(HDL-C)level and the risk of clinical events resulting from atherosclerosis is widely accepted.Therefore,targeting HDL therapeutically presents an attractive strategy for treating atherosclerotic cardiovascular disease.However,multiple epidemiological evidences have demonstrated that raising HDL-C does not certainly confer a clinical benefit.The cholesterol content of HDL may provide limited information on their antiatherogenic properties and the composition and particles’structure provide more information on their functionality.HDL particles are,however,highly heterogeneous in structure and intravascular metabolism.Many critical proteins and enzymes have been discovered to regulate the levels,composition and structure of HDL.This paper mainly reviews the effects of various molecules on HDL metabolism and remodeling processes,as well as the research progress of related drugs targeting the above processes.Based on the relationship between HDL and RCT,we reviewed four aspects of AS therapeutic strategies for HDL modulation:(1)promoting cholesterol efflux from peripheral cells;(2)enhancing HDL esterification;(3)influencing HDL remodeling;(4)affecting hepatic uptake and intestinal excretion of HDL,which may provide a theoretical reference for a more comprehensive evaluation of the antiatherogenic effects of HDL.