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.

肥胖伴随着血浆游离脂肪酸（FFA）升高，进而诱发胰岛素抵抗和 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 炎症细胞和局部细胞类型，包括内皮细胞和心肌细胞 (CM)，在 在介导纤维化、肥大、舒张功能障碍和胰岛素抵抗中发挥作用，从而促进 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 糖尿病心肌病的发病机制及其潜在机制尚不清楚。此外， 与全身炎症相比，局部机制的重要性仍有待阐明。我们的 初步结果表明，FFA 通过 PPARα-NF-βB 依赖性激活 CM 中 IL-6 的产生 机制，进而促进糖尿病心肌病的发展。在这项研究中，我们将澄清 CM 中 PPARα 和 IL-6 在介导高脂饮食 (HFD) 引起的心功能障碍中的作用 消耗以及升高的 FFA 刺激 CM 中 IL-6 的分子机制。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。血浆 FFA 的增加通过增加直接刺激 CM 中的 IL-6 转录 PPARα-NF-βB 异二聚体与位于 IL-6 启动子中的 NF-β 元件结合。 IL-6 产生于 CM 作为自分泌/旁分泌因子诱发糖尿病心肌病。目标 1：阐明 心脏内源性 PPARα 和 IL-6 在介导糖尿病心肌病的初始发展中的作用。目标 2： 阐明 PPARα 刺激 CM 中 IL-6 转录的分子机制。目标 3：评估 抑制 PPARα-NF-βB 异二聚体形成是否会抑制 CM 产生 IL-6 和 食用 HFD 会导致糖尿病性心肌病的发生。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。