Regulation by Leptin of Vascular Smooth Muscle Cells Proliferation and Migration

肥胖是心血管疾病的主要危险因素之一。然而，对肥胖与心血管疾病之间的分子机制知之甚少。肥胖基因的产物瘦素被定义为食物摄入和能量消耗的调节剂。瘦素受体（OB-R）在全身广泛表达，提示瘦素除了控制食物摄入和体重外，还可能具有其他重要的生理功能。在肥胖患者中，血浆瘦素水平升高。因此，在本研究中，我们研究了瘦素对血管平滑肌细胞（VSMC）功能的影响。培养的大鼠主动脉VSMC表达瘦素受体的几种亚型，包括130 kDa的短型。瘦素刺激VSMC增殖和迁移。瘦素刺激细胞外调节激酶（ERK）的有丝分裂原活化蛋白（MAP）激酶亚型的磷酸化和激活，也增加了VSMC中抗磷酸酪氨酸免疫沉淀的磷脂酰肌醇（PI）3-激酶活性。此外，两种不同的PI 3-激酶抑制剂，wortmannin和LY 294002抑制瘦素的迁移作用，表明PI 3-激酶在瘦素刺激的VSMC迁移中的重要作用。这些结果表明，瘦素是VSMC的增殖和迁移因子，提示瘦素在血管病变的形成和发展中起作用。

Obesity is one of the major risk factors for cardiovascular diseases. However, less is yet known about the molecular mechanisms associating between obesity and cardiovascular diseases. The ob gene product, leptin has been defined as a regulator of food intake and energy expenditure. The receptors for leptin (OB-R) are widely expressed throughout the body, suggesting that, in addition to the control of food intake and body weight, leptin may have other important physiological functions. In obese patients, plasma leptin levels are elevated. Therefore, in this study, we investigated the effect of leptin on vascular smooth muscle cell (VSMC) functions. Cultured rat aortic VSMC expressed several isoforms of leptin receptors including 130-kDa short form. Leptin stimulated both proliferation and migration of VSMC. Leptin stimulated phosphorylation and activation of extracellular-regulated Kinase (ERK) isoformes of mitogen-activated protein (MAP) kinases, and also increased phosphatidylinositol (PI) 3-kinase activity in anti-phosphotyrosine immunoprecipitates in VSMC. Further, two distinct PI 3-kinase inhibitors, wortmannin and LY294002 inhibited the migratory effect of leptin, indicating the essential role of PI 3-kinase in leptin-stimulated migration of VSMC. These results demonstrate that leptin is a proliferative and migratory factor for VSMC, implying that leptin plays a role in the formation and development of vascular lesions.