Adipocytes and cardiac remodeling

脂肪细胞和心脏重塑

• 批准号: 9198055
• 负责人: Ju Chen
• 金额: $ 38.75万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-12-21 至 2019-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9198055
• 关键词: Ablation; Adipocytes; Adipose tissue; Adverse effects; Affect; Agonist; Attenuated; Bioinformatics; Cardiac; Cardiac Myocytes; Cardiomyopathies; Cell Communication; Cells; Clinic; Coculture Techniques; Communication; Data; Diet; Disease; Endocrine Glands; Experimental Models; FRAP1 gene; Family; Functional disorder; Gene Expression; Genetic; Genetic Transcription; Glycogen; Goals; Heart Hypertrophy; Heart failure; Homeostasis; Hormones; Hypertrophy; In Vitro; Investigation; Knockout Mice; Lead; Lipids; Mediating; Messenger RNA; MicroRNAs; Modeling; Molecular; Mus; Muscle Cells; Non-Insulin-Dependent Diabetes Mellitus; Nuclear; Nuclear Hormone Receptors; Nucleotides; Obesity; Organ; Oxidative Stress; Pathogenicity; Pathway interactions; Peroxisome Proliferator-Activated Receptors; Play; Receptor Signaling; Role; Secretory Vesicles; Serum; Signal Transduction; Site; System; Therapeutic Uses; Tissues; Translations; Transport Vesicles; Untranslated RNA; Up-Regulation; Ventricular; clinical application; cytokine; exosome; extracellular; in vivo; insight; insulin sensitivity; insulin sensitizing drugs; lipid biosynthesis; lipid metabolism; member; mouse model; novel; overexpression; public health relevance; receptor expression; rosiglitazone

 DESCRIPTION (provided by applicant): Rosiglitazone (RSG) is a synthetic agonist of the nuclear hormone Peroxisome Proliferator-Activated Receptor-  (PPAR-) and has been successfully used in the clinic for type 2 diabetes as an insulin-sensitizer. However, adverse cardiac side effects have seriously hindered its clinical application. Existing evidence from experimental models revealed that RSG results in cardiac hypertrophy, which may lead to heart failure. Currently, molecular mechanisms underlying RSG-induced cardiac hypertrophy remain unclear. Adipose tissue is a major site of PPAR- expression and function. Our preliminary dat showed that activation of PPAR- by RSG in adipocytes in a co-culture system resulted in cardiomyocyte hypertrophy. Furthermore, ablation of PPAR- in adipocytes attenuated RSG-induced cardiac hypertrophy in vivo. These data imply a functional interplay between adipose and cardiac tissue that regulates cardiac hypertrophy. Adipose tissue plays a critical role as an endocrine organ, and secretes cytokines that regulate systemic homeostasis and the function of other organs. Interestingly, a recent screen as well as our preliminary data revealed that adipocytes are able to release microRNAs (miRs). miRs are a family of highly conserved, small (~22 nucleotide) noncoding RNAs that post-transcriptionally repress gene expression by degrading or inhibiting translation of their target mRNA. The discovery of circulating extracellula miRs in serum suggests they may play a novel role in mediating cell-cell communication. Exosomes are the major transport vesicle of secretory miRs, allowing miR transfer and genetic exchange between cells. Our preliminary studies demonstrated that RSG stimulation of PPAR- signaling in adipocytes leads to upregulation of the miR-200a/b/429 cluster, and secretion o mature miR-200a in exosomes. Bioinformatics analysis and experimental investigation demonstrated that miR-200a can target components of the mTOR pathway, which regulates cardiac hypertrophy. In addition, we found that miR-200a was upregulated in a diet-induced obesity-associated cardiomyopathy model. The aforementioned suggest our overall hypothesis is that circulating members of the miR-200a/b/429 cluster mediate communication between adipose and cardiac tissue to adversely affect cardiac remodeling in two distinct models of cardiomyopathy. The overall goal of this project is to elucidate molecular mechanisms underlying adverse cardiac remodeling induced by adipose tissue, and provide insights into a novel exosomal miR-mediated pathway between adipose and cardiac tissue. Accordingly, our Specific Aims are: 1. To examine whether all members of the miR-200a/b/429 cluster are transported from adipocytes to cardiomyocytes in exosomes and to determine potential functional consequences of this in vitro; 2. To elucidate the role of miR-200a and the miR-200a/b/429 cluster in RSG-mediated cardiac hypertrophy in vivo by using adipocyte-specific knockout mouse models; and 3. To understand pathophysiological effects of miR-200a and the miR-200a/b/429 cluster in a mouse model of obesity-associated cardiomyopathy using adipocyte-specific knockout mice.

 描述（申请人提供）：罗格列酮（RSG）是核激素过氧化物酶体增殖物激活受体-（PPAR-）的合成激动剂，已作为胰岛素增敏剂成功应用于2型糖尿病的临床。然而，不良的心脏副作用严重阻碍了其临床应用，现有的实验模型证据表明，RSG 会导致心脏肥大，从而可能导致心脏肥大。目前，RSG 诱导的心脏肥大的分子机制仍不清楚。脂肪组织是 PPAR- 表达和功能的主要部位。我们的初步数据表明，RSG 在脂肪细胞中激活 PPAR-。培养系统导致心肌细胞肥大此外，脂肪细胞中 PPAR-β 的消融减弱了 RSG 诱导的体内心脏肥大。脂肪和心脏组织之间的功能相互作用调节心脏肥大脂肪组织作为内分泌器官发挥着关键作用，并分泌调节全身稳态和其他器官功能的细胞因子，最近的筛查以及我们的初步数据表明。脂肪细胞能够释放 microRNA (miR) 是一个高度保守的小（约 22 个核苷酸）非编码 RNA 家族，可通过转录后抑制基因表达。血清中循环细胞外 miR 的发现表明，外泌体可能在介导细胞间通讯中发挥新作用，是分泌性 miR 的主要转运囊泡，允许细胞之间的 miR 转移和遗传交换。我们的初步研究表明，RSG 刺激脂肪细胞中的 PPAR- 信号传导导致 miR-200a/b/429 簇上调，并分泌成熟脂肪细胞。外泌体中的 miR-200a。生物信息学分析和实验研究表明，miR-200a 可以靶向调节心脏肥大的 mTOR 通路的成分。此外，我们发现 miR-200a 在饮食诱导的肥胖相关心肌病模型中上调。上述内容表明我们的总体假设是，miR-200a/b/429 簇的循环成员介导脂肪和心脏组织之间的通讯，从而对心脏产生不利影响。该项目的总体目标是阐明脂肪组织诱导的不良潜在心脏重塑的分子机制，并提供对脂肪和心脏组织之间新型外泌体 miR 介导的途径的见解。 1. 检查 miR-200a/b/429 簇的所有成员是否在外泌体中从脂肪细胞转运至心肌细胞，并确定其体外潜在的功能后果； 2. 通过使用脂肪细胞特异性敲除小鼠模型，阐明 miR-200a 和 miR-200a/b/429 簇在 RSG 介导的体内心脏肥大中的作用；以及 3. 了解 miR-200a 和 miR-200a/b/429 簇的病理生理学作用；使用脂肪细胞特异性敲除小鼠的肥胖相关心肌病小鼠模型中的 miR-200a/b/429 簇。