Centre for Molecular and Vascular Biology, Department of Cardiovascular Medicine, Catholic University of Leuven, Campus Gasthuisberg, Herestraat 49, 3000 Leuven, Belgium.
Curr Mol Med. 2014 May;14(4):481-503. doi: 10.2174/1566524013666131118113927.
Plasma levels of high density lipoprotein (HDL) cholesterol levels and of apolipoprotein A-I are inversely correlated with the incidence of coronary heart disease. According to the HDL hypothesis, raising HDL cholesterol is expected to lead to a decrease of coronary heart disease risk. The stringent requirement for proving or refuting this hypothesis is that the causal pathway between the therapeutic intervention and a hard clinical end-point obligatory passes through HDL. The lack of positive clinical results in several recent HDL trials should be interpreted in light of the poor HDL specificity of the drugs that were investigated in these trials. Nevertheless, the results of Mendelian randomization studies further raise the possibility that the epidemiological relationship between HDL cholesterol and coronary artery disease might reflect residual confounding. HDL are circulating multimolecular platforms that exert divergent functions: reverse cholesterol transport, antiinflammatory effects, anti-oxidative effects, immunomodulatory effects, improved endothelial function, increased endothelial progenitor cell number and function, antithrombotic effects, and potentiation of insulin secretion and improvement of insulin sensitivity. Pleiotropic effects of HDL might be translated in clinically significant effects in strategically selected therapeutic areas that are not directly related to native coronary artery disease. In this review, four new therapeutic areas for HDL-targeted diseases are presented: critical illness, allograft vasculopathy and vein graft atherosclerosis, type 2 diabetes mellitus, and heart failure. The strategic selection of these therapeutic areas is not only based on specific functional properties of HDL but also on significant pre-clinical and clinical data that support this choice.
高密度脂蛋白（HDL）胆固醇水平和载脂蛋白 A-I 的血浆水平与冠心病的发病率呈负相关。根据 HDL 假说，升高 HDL 胆固醇有望降低冠心病风险。证明或反驳这一假说的严格要求是，治疗干预与硬性临床终点之间的因果途径必须通过 HDL。最近几项 HDL 试验中缺乏积极的临床结果，应该根据这些试验中研究的药物对 HDL 的特异性差来解释。然而，孟德尔随机化研究的结果进一步增加了这样一种可能性，即 HDL 胆固醇与冠心病之间的流行病学关系可能反映了残余混杂因素。HDL 是循环的多分子平台，发挥着不同的功能：胆固醇逆转运、抗炎作用、抗氧化作用、免疫调节作用、改善内皮功能、增加内皮祖细胞数量和功能、抗血栓作用以及增强胰岛素分泌和改善胰岛素敏感性。HDL 的多效性可能会转化为在与原发性冠状动脉疾病无直接关系的战略性选择治疗领域中具有临床意义的效果。在这篇综述中，提出了四个针对 HDL 靶向疾病的新治疗领域：危重病、同种异体移植物血管病和静脉移植物动脉粥样硬化、2 型糖尿病和心力衰竭。这些治疗领域的战略选择不仅基于 HDL 的特定功能特性，还基于支持这一选择的重要临床前和临床数据。
