PPARα induces IL-6 to trigger diabetic cardiomyopathy

PPARα 诱导 IL-6 引发糖尿病心肌病

• 批准号: 10317052
• 负责人: Junichi Sadoshima
• 金额: $ 55.9万
• 依托单位: RBHS-NEW JERSEY MEDICAL SCHOOL
• 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 2022-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10317052
• 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; Failure; Fatty Acids; Fatty acid glycerol esters; Fibroblasts; Fibrosis; Functional disorder; Genetic Transcription; Glycogen Synthase Kinase 3; Heart; Heart failure; High Fat Diet; Hypertrophy; Immune; Inflammation; Inflammatory; Inflammatory Infiltrate; Insulin Resistance; Interleukin-1; Interleukin-6; Intervention; Knowledge; Laboratories; Lead; Left Ventricular Hypertrophy; Ligands; Mediating; Metabolic syndrome; Modality; Modeling; Molecular; Mus; Myocardial dysfunction; Non-Insulin-Dependent Diabetes Mellitus; Nonesterified Fatty Acids; Obesity; PPAR alpha; Patients; Peroxisome Proliferator-Activated Receptors; 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.

Obesity is accompanied by elevated plasma free fatty acid (FFA), which, in turn, induces insulin resistance and 糖尿病。 More than half of diabetic patients develop myocardial dysfunction, known as diabetic 心肌病，其特征为左心室肥厚、纤维化和舒张功能障碍。部分患者 发展为射血分数保留的心力衰竭（HFpEF）。因此，阐明了潜在的分子 糖尿病心肌病的发生机制至关重要。肥胖患者的心脏，胰岛素 抵抗力、II 型糖尿病和 HFpEF 通常会出现低度炎症。促炎细胞因子 和趋化因子，包括脂肪组织中产生的 TNF-α、IL-1α、IL-6 和 MCP-1，浸润 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 糖尿病心肌病的发展。然而，哪些细胞类型在初始阶段产生细胞因子 of diabetic cardiomyopathy and what the underlying mechanism is are poorly understood.此外， significance of the local mechanisms compared to systemic inflammation remains to be clarified.我们的 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.在这项研究中，我们将澄清 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.我们的整体 假设是： CM 中的 PPARα 是 FFA 增加的传感器，通过以下途径引发糖尿病心肌病： IL-6的产生。 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 产生于 CMs acts as an autocrine/paracrine factor to induce diabetic cardiomyopathy.目标 1：阐明 cardiac endogenous PPAR and IL-6 in mediating the initial development of diabetic cardiomyopathy.目标 2： 阐明 PPARα 刺激 CM 中 IL-6 转录的分子机制。目标 3：评估 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.我们将使用以下方法解决这些问题 新生成的 CM 特异性功能丧失小鼠模型。此外，我们将获得概念验证 PPARα-NF-βB异二聚体是糖尿病心肌病的新型治疗靶点。我们期望我们的研究 应证明一种刺激 CM 中局部先天产生 IL-6 的新机制及其在 介导糖尿病心肌病的初始发展，这与许多患有糖尿病的患者高度相关 肥胖和边缘代谢综合征。