Bodart V, Febbraio M, Demers A, McNicoll N, Pohankova P, Perreault A, Sejlitz T, Escher E, Silverstein R L, Lamontagne D, Ong H
Faculty of Pharmacy and Department of Pharmacology, Université de Montréal, Montreal, Canada.
Circ Res. 2002 May 3;90(8):844-9. doi: 10.1161/01.res.0000016164.02525.b4.
Growth hormone-releasing peptides (GHRPs) are known as potent growth hormone secretagogues whose actions are mediated by the ghrelin receptor, a G protein-coupled receptor cloned from pituitary libraries. Hexarelin, a hexapeptide of the GHRP family, has reported cardiovascular activity. To identify the molecular target mediating this activity, rat cardiac membranes were labeled with a radioactive photoactivatable derivative of hexarelin and purified using lectin affinity chromatography and preparative gel electrophoresis. A binding protein of M(r) 84 000 was identified. The N-terminal sequence determination of the deglycosylated protein was identical to rat CD36, a multifunctional glycoprotein, which was expressed in cardiomyocytes and microvascular endothelial cells. Activation of CD36 in perfused hearts by hexarelin was shown to elicit an increase in coronary perfusion pressure in a dose-dependent manner. This effect was lacking in hearts from CD36-null mice and hearts from spontaneous hypertensive rats genetically deficient in CD36. The coronary vasoconstrictive response correlated with expression of CD36 as assessed by immunoblotting and covalent binding with hexarelin. These data suggest that CD36 may mediate the coronary vasospasm seen in hypercholesterolemia and atherosclerosis.
生长激素释放肽（GHRPs）是一类强效的生长激素促分泌素，其作用由胃动素受体介导，该受体是一种从垂体文库中克隆出的G蛋白偶联受体。生长激素释放肽六肽（Hexarelin）是GHRP家族的一种六肽，已报道具有心血管活性。为了确定介导这种活性的分子靶点，用Hexarelin的放射性光活化衍生物标记大鼠心脏膜，并通过凝集素亲和色谱和制备性凝胶电泳进行纯化。鉴定出一种分子量为84000的结合蛋白。去糖基化蛋白的N端序列测定与大鼠CD36相同，CD36是一种多功能糖蛋白，在心肌细胞和微血管内皮细胞中表达。研究表明，Hexarelin激活灌注心脏中的CD36会以剂量依赖的方式引起冠状动脉灌注压升高。在CD36基因敲除小鼠的心脏以及基因缺陷型自发性高血压大鼠的心脏中未观察到这种效应。通过免疫印迹和与Hexarelin的共价结合评估，冠状动脉血管收缩反应与CD36的表达相关。这些数据表明，CD36可能介导高胆固醇血症和动脉粥样硬化中出现的冠状动脉痉挛。
