脂肪细胞microRNA外分泌体介导罗格列酮促进心肌肥大的新机制

项目名称： 脂肪细胞microRNA外分泌体介导罗格列酮促进心肌肥大的新机制

项目编号： No.81470373

项目类型： 面上项目

立项/批准年度： 2015

项目学科： 医药、卫生

项目作者： 汪南平

作者单位： 北京大学

项目金额： 73万元

中文摘要： 罗格列酮(RSG)是核受体过氧化酶体增殖物激活受体γ（PPARγ）的选择性合成配体，通过改善组织胰岛素敏感性发挥良好的降糖作用。然而，其心血管副作用严重限制了临床应用。动物实验及临床研究表明罗格列酮促心肌肥大的作用可能是其增加心衰风险的原因之一。我们前期研究提示：罗格列酮可能激活脂肪组织中微小RNA（miR）表达，通过外分泌体（exosome）作用于心肌细胞的肥大反应相关通路，从而发挥促心肌肥大的作用。本课题围绕这一假说开展工作：1）阐明脂肪组织PPARγ在RSG致心肌肥大的作用；2）明确外分泌体miR作为传递脂肪组织对心脏调节作用的一种新方式；3）探讨RSG及PPARγ对脂肪组织及其外分泌体的miR谱的影响；4）研究脂肪组织外分泌体调节心肌肥大的关键miR及其靶分子和靶通路。本课题将阐明RSG心脏不良反应的病理生理学机制并揭示脂肪-心脏组织相互作用的新的调控方式。

中文关键词： 心肌肥大；微小RNA；罗格列酮

英文摘要： Rosiglitazone, a synthetic ligand selective for the nuclear receptor peroxisome proliferator-activated receptor-γ?(PPARγ), improves insulin sensitivity and reduces hyperglycemia. However, the adverse cardiovascular effects have seriously hindered its clinical application. Existing evidence from experimental models and clinical subjects, although contradictory, revealed that rosiglitazone increases cardiac hypertrophy, which may contribute to the increased risk for the heart failure. Our preliminary studies suggest that rosiglitazone may activate adipose microRNAs, which are secreted into circulation and transported via exosomes, act in cardiomyocytes and exert the pro-hypertrophic effect. We will examine this hypothesis by addressing the following specific aims: 1) examine the central role of PPARγ in adipose in rosiglitazone induction of cardiac hypertrophy; 2) investigate the actions of the adipocyte-derived exosomal microRNAs as a novel mechanism for the fat-heart crosstalk; 3) define the rosiglitazone- and PPARγ-regulated microRNA signatures in the adipose tissue and the adipose-derived exosomes; and 4) characterize the key exosomal microRNAs, their target genes and pathways involved in cardiac hypertrophy. These studies will elucidate the pathophysiological mechanisms underlying the adverse cardiac effects of TZDs and provide novel insights into the interaction between the adipose tissues and heart.

英文关键词： myocardial hypertrophy;microRNA;rosiglitazone