Yuhanna I S, Zhu Y, Cox B E, Hahner L D, Osborne-Lawrence S, Lu P, Marcel Y L, Anderson R G, Mendelsohn M E, Hobbs H H, Shaul P W
Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas, Texas, USA.
Nat Med. 2001 Jul;7(7):853-7. doi: 10.1038/89986.
Atherosclerosis is the primary cause of cardiovascular disease, and the risk for atherosclerosis is inversely proportional to circulating levels of high-density lipoprotein (HDL) cholesterol. However, the mechanisms by which HDL is atheroprotective are complex and not well understood. Here we show that HDL stimulates endothelial nitric oxide synthase (eNOS) in cultured endothelial cells. In contrast, eNOS is not activated by purified forms of the major HDL apolipoproteins ApoA-I and ApoA-II or by low-density lipoprotein. Heterologous expression experiments in Chinese hamster ovary cells reveal that scavenger receptor-BI (SR-BI) mediates the effects of HDL on the enzyme. HDL activation of eNOS is demonstrable in isolated endothelial-cell caveolae where SR-BI and eNOS are colocalized, and the response in isolated plasma membranes is blocked by antibodies to ApoA-I and SR-BI, but not by antibody to ApoA-II. HDL also enhances endothelium- and nitric-oxide-dependent relaxation in aortae from wild-type mice, but not in aortae from homozygous null SR-BI knockout mice. Thus, HDL activates eNOS via SR-BI through a process that requires ApoA-I binding. The resulting increase in nitric-oxide production might be critical to the atheroprotective properties of HDL and ApoA-I.
动脉粥样硬化是心血管疾病的主要病因，而动脉粥样硬化的风险与循环中的高密度脂蛋白（HDL）胆固醇水平呈负相关。然而，HDL具有抗动脉粥样硬化作用的机制很复杂，尚未完全明确。在此我们表明，HDL可刺激培养的内皮细胞中的内皮型一氧化氮合酶（eNOS）。相比之下，主要的HDL载脂蛋白ApoA-I和ApoA-II的纯化形式以及低密度脂蛋白均不能激活eNOS。在中国仓鼠卵巢细胞中的异源表达实验表明，清道夫受体BI（SR-BI）介导了HDL对该酶的作用。在SR-BI和eNOS共定位的分离的内皮细胞小窝中可证实HDL对eNOS的激活作用，并且分离的质膜中的反应被抗ApoA-I和SR-BI的抗体阻断，但不被抗ApoA-II的抗体阻断。HDL还可增强野生型小鼠主动脉中内皮依赖性和一氧化氮依赖性舒张，但对纯合SR-BI基因敲除小鼠的主动脉无此作用。因此，HDL通过一种需要ApoA-I结合的过程经由SR-BI激活eNOS。由此导致的一氧化氮生成增加可能对HDL和ApoA-I的抗动脉粥样硬化特性至关重要。
