Division of Cardiovascular Medicine, University of Pennsylvania, Penn Tower, 6th Floor, 3400 Spruce Street, Philadelphia, PA 19104, USA.
Nat Rev Cardiol. 2011 May;8(5):266-77. doi: 10.1038/nrcardio.2010.200. Epub 2011 Jan 18.
The burden of atherothrombotic cardiovascular disease remains high despite currently available optimum medical therapy. To address this substantial residual risk, the development of novel therapies that attempt to harness the atheroprotective functions of HDL is a major goal. These functions include the critical role of HDL in reverse cholesterol transport, and its anti-inflammatory, antithrombotic, and antioxidant activities. Discoveries in the past decade have shed light on the complex metabolic and antiatherosclerotic pathways of HDL. These insights have fueled the development of HDL-targeted drugs, which can be classified among four different therapeutic approaches: directly augmenting apolipoprotein A-I (apo A-I) levels, such as with apo A-I infusions and upregulators of endogenous apo A-I production; indirectly augmenting apo A-I and HDL-cholesterol levels, such as through inhibition of cholesteryl ester transfer protein or endothelial lipase, or through activation of the high-affinity niacin receptor GPR109A; mimicking the functionality of apo A-I with apo A-I mimetic peptides; and enhancing steps in the reverse cholesterol transport pathway, such as via activation of the liver X receptor or of lecithin-cholesterol acyltransferase.
尽管目前有最佳的药物治疗，但动脉粥样硬化性心血管疾病的负担仍然很高。为了应对这一巨大的剩余风险，开发新的治疗方法以试图利用高密度脂蛋白（HDL）的动脉保护功能是一个主要目标。这些功能包括 HDL 在胆固醇逆转运中的关键作用，以及其抗炎、抗血栓和抗氧化作用。在过去十年中的发现揭示了 HDL 的复杂代谢和抗动脉粥样硬化途径。这些见解推动了针对 HDL 的药物的发展，这些药物可以分为四种不同的治疗方法：直接增加载脂蛋白 A-I（apo A-I）水平，例如使用 apo A-I 输注和内源性 apo A-I 产生的上调剂；间接增加 apo A-I 和 HDL-胆固醇水平，例如通过抑制胆固醇酯转移蛋白或内皮脂肪酶，或通过激活高亲和力烟酰胺受体 GPR109A；用 apo A-I 模拟肽模拟 apo A-I 的功能；以及增强胆固醇逆转运途径中的步骤，例如通过激活肝 X 受体或卵磷脂胆固醇酰基转移酶。
