PPARα induces IL-6 to trigger diabetic cardiomyopathy

PPARα 诱导 IL-6 引发糖尿病心肌病

• 批准号: 10534143
• 负责人: Junichi Sadoshima
• 金额: $ 55.9万
• 依托单位: RUTGERS BIOMEDICAL AND HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-12-01 至 2024-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10534143
• 关键词: Address; Adipose tissue; Binding; Blood; CCL2 gene; Cardiac; Cardiac Myocytes; Cardiovascular Diseases; Cause of Death; Cell Nucleus; Cells; Consumption; Development; Diabetes Mellitus; EFRAC; Elements; Endothelial Cells; Fatty Acids; Fatty acid glycerol esters; Fibroblasts; Fibrosis; Functional disorder; Genetic Transcription; Heart; Heart failure; High Fat Diet; Hypertrophy; Immune; Inflammation; Inflammatory; Inflammatory Infiltrate; Insulin Resistance; Interleukin-6; Intervention; Knockout Mice; Knowledge; Laboratories; Lead; Left Ventricular Hypertrophy; Ligands; Mediating; Metabolic syndrome; Modality; Modeling; Molecular; Mus; Myocardial dysfunction; NF-kappa B; Non-Insulin-Dependent Diabetes Mellitus; Nonesterified Fatty Acids; Obesity; PPAR alpha; Patients; Phase; Phosphorylation; Plasma; Play; Prevalence; Process; Production; Risk Factors; Role; TNF gene; TNFRSF5 gene; Testing; autocrine; cell type; chemokine; cytokine; diabetic cardiomyopathy; diabetic patient; disability-adjusted life years; functional disability; heart cell; high body mass index; loss of function; mitochondrial dysfunction; mouse model; new therapeutic target; novel; obese patients; obese person; paracrine; preservation; promoter; response; sensor; systemic inflammatory response

Obesity is accompanied by elevated plasma free fatty acid (FFA), which, in turn, induces insulin resistance and diabetes. More than half of diabetic patients develop myocardial dysfunction, known as diabetic cardiomyopathy, characterized by left ventricular hypertrophy, fibrosis and diastolic dysfunction. Some patients develop heart failure with preserved ejection fraction (HFpEF). Thus, elucidating the underlying molecular mechanism of diabetic cardiomyopathy is critically important. The hearts of patients with obesity, insulin resistance, type II diabetes, and HFpEF often develop a low grade of inflammation. Pro-inflammatory cytokines and chemokines, including TNF-, IL-1, IL-6, and MCP-1, produced in adipose tissues, infiltrating inflammatory cells, and local cell types, including endothelial cells and cardiomyocytes (CMs), play an essential role in mediating fibrosis, hypertrophy, diastolic dysfunction and insulin resistance, thereby contributing to the development of diabetic cardiomyopathy. However, which cell types produce cytokines during the initial phase of diabetic cardiomyopathy and what the underlying mechanism is are poorly understood. Furthermore, the significance of the local mechanisms compared to systemic inflammation remains to be clarified. Our preliminary results suggest that FFA activates IL-6 production in CMs through a PPAR-NF-B-dependent mechanism, which, in turn, promotes the development of diabetic cardiomyopathy. In this study, we will clarify the role of PPAR and IL-6 in CMs in mediating cardiac dysfunction in response to high fat diet (HFD) consumption and the molecular mechanisms through which elevated FFA stimulates IL-6 in CMs. Our overall hypotheses are: PPAR in CMs is a sensor of increased FFA that triggers diabetic cardiomyopathy through production of IL-6. Increases in plasma FFA directly stimulates IL-6 transcription in CMs through increased binding of PPAR-NF-B heterodimer to the NF-B element located in the IL-6 promoter. IL-6 produced in CMs acts as an autocrine/paracrine factor to induce diabetic cardiomyopathy. Aim 1: Elucidate the role of cardiac endogenous PPAR and IL-6 in mediating the initial development of diabetic cardiomyopathy. Aim 2: Elucidate the molecular mechanism by which PPARstimulates transcription of IL-6 in CMs. Aim 3: Evaluate whether suppression of PPAR-NF-B heterodimer formation inhibits CM production of IL-6 and the development of diabetic cardiomyopathy in response to HFD consumption. We will address these issues using newly generated CM-specific loss-of-function mouse models. In addition, we will obtain a proof-of-concept that PPAR-NF-B heterodimer is a novel therapeutic target for diabetic cardiomyopathy. We expect that our study should demonstrate a novel mechanism stimulating local innate production of IL-6 in CMs and its role in mediating the initial development of diabetic cardiomyopathy which is highly relevant to many patients with obesity and borderline metabolic syndrome.

肥胖症伴随着升高的血浆脂肪酸（FFA），这反过来诱导胰岛素抵抗和 糖尿病。超过一半的糖尿病患者出现心肌功能障碍，称为糖尿病 心肌病，其特征是左心室肥大，纤维化和舒张功能障碍。一些患者 通过保留的射血分数（HFPEF）发展心力衰竭。阐明了基础分子 糖尿病心肌病的机制至关重要。肥胖，胰岛素患者的心脏 电阻，II型糖尿病和HFPEF通常会出现低级的炎症。促炎性细胞因子 和趋化因子，包括TNF-，IL-1，IL-6和MCP-1，在脂肪组织中产生，浸润 炎症细胞和局部细胞类型，包括内皮细胞和心肌细胞（CMS），起着必不可少的 在介导纤维化，肥大，舒张功能障碍和胰岛素抵抗中的作用，从而有助于 糖尿病心肌病的发展。但是，哪种细胞类型在初始阶段产生细胞因子 糖尿病心肌病以及基本机制的理解较低。此外， 与全身感染相比，局部机制的重要性尚待澄清。我们的 初步结果表明，FFA通过PPAR-NF-B依赖性激活CMS中的IL-6产生 机制又促进了糖尿病心肌病的发展。在这项研究中，我们将澄清 PPAR和IL-6在CMS中的作用在响应高脂肪饮食（HFD）的心脏功能障碍中 消耗和升高FFA刺激CMS IL-6的分子机制。我们的整体 假设是：CMS中的PPAR是FFA增加的传感器，可触发糖尿病性心肌病。 IL-6的生产。血浆FFA的增加直接通过增加而直接刺激CMS中的IL-6转录 PPAR-NF-B异二聚体与位于IL-6启动子中的NF-B元件的结合。 IL-6产生 CMS充当自分泌/旁分泌因子诱导糖尿病心肌病。目标1：阐明 心脏内源性PPAR和IL-6在介导糖尿病心肌病的初步发展时。目标2： 阐明了PPAR刺激CMS中IL-6的转录的分子机制。目标3：评估 PPAR-NF-B异二聚体的抑制是否抑制IL-6的CM产生 针对HFD消耗的糖尿病心肌病的发展。我们将使用 新生成的CM特异性功能丧失鼠标模型。此外，我们还将获得概念证明 PPAR-NF-B异二聚体是糖尿病心肌病的新型治疗靶点。我们希望我们的研究 应该证明一种新型机制，刺激CMS中IL-6的本地先天生产及其在 介导糖尿病心肌病的初步发展，这与许多患者高度相关 肥胖和边缘代谢综合征。