Adipocytes and cardiac remodeling

脂肪细胞和心脏重塑

• 批准号: 9010674
• 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/9010674
• 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; 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; Pathway interactions; Peroxisome Proliferator-Activated Receptors; Play; Receptor Signaling; Role; Serum; Signal Transduction; Site; System; Therapeutic Uses; Tissues; Translations; Transport Vesicles; Untranslated RNA; Up-Regulation; Ventricular; clinical application; cytokine; exosome; experimental analysis; 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（由应用程序提供）：罗格列酮（RSG）是核马酮过氧化物酶体增殖物激活的受体（PPAR-）的合成激动剂，并已在诊所成功使用了2型糖尿病型糖尿病，作为胰岛素敏感剂。但是，不良心脏副作用严重阻碍了其临床应用。实验模型的现有证据表明，RSG导致心脏肥大，这可能导致心力衰竭。当前，RSG诱导的心脏肥大的分子机制尚不清楚。脂肪组织是PPAR-表达和功能的主要部位。我们的初步DAT表明，在共培养系统中，RSG在脂肪细胞中的PPAR-激活导致心肌细胞肥大。此外，脂肪细胞中PPAR-的消融减弱了RSG诱导的心肥大。这些数据暗示脂肪和心脏组织之间的功能相互作用，可以调节心脏肥大。脂肪组织作为内分泌器官起着至关重要的作用，并分泌调节全身稳态和其他器官功能的细胞因子。有趣的是，最近的屏幕以及我们的初步数据表明，脂肪细胞能够释放microRNA（miR）。 miR是一个高度保守的小（〜22个核苷酸）非编码RNA的家族，在转录后通过降解或抑制其靶mRNA的翻译来反映基因表达。在血清中发现循环外旋转的miR表明它们可能在介导细胞 - 细胞通信中起新颖的作用。外泌体是秘书mir的主要运输场所，允许miR转移和细胞之间的遗传交换。我们的初步研究表明，脂肪细胞中PPAR-信号传导的RSG模拟导致miR-200a/b/429簇的上调，而外泌体中的MiR-200a分泌O成熟。生物信息学分析和实验研究表明，miR-200a可以靶向MTOR途径的成分，该途径调节心脏肥大。此外，我们发现MiR-200a在饮食引起的肥胖相关心肌病模型中进行了更新。理由表明我们的总体假设是，脂肪和心脏组织之间的miR-200a/b/429群集介质通信的循环成员在两种不同的心肌病模型中对心脏重塑产生不利影响。该项目的总体目标是阐明由脂肪组织诱导的不良心脏重塑的基础分子机制，并为脂肪和心脏组织之间的新型外泌体miR介导的途径提供见解。根据我们的具体目的是：1。检查miR-200a/b/429簇的所有成员是否均从外泌体中从脂肪细胞转移到心肌细胞，并确定体外的潜在功能后果； 2。通过使用脂肪细胞特异性的基因敲除小鼠模型，阐明了miR-200a和miR-200a/b/429簇在RSG介导的心脏肥大中的作用；和3。使用脂肪细胞特异性敲除小鼠，在肥胖相关的心肌病小鼠模型中，miR-200a和miR-200a/b/429簇的病理生理效应。