PPARα induces IL-6 to trigger diabetic cardiomyopathy

PPARα 诱导 IL-6 引发糖尿病心肌病

• 批准号: 10062516
• 负责人: Junichi Sadoshima
• 金额: $ 55.7万
• 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 2023-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10062516
• 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.

肥胖伴随着血浆游离脂肪酸（FFA）升高，这反过来又诱导胰岛素抵抗， 糖尿病超过一半的糖尿病患者会出现心肌功能障碍，称为糖尿病性心脏病。 心肌病，以左心室肥大、纤维化和舒张功能障碍为特征。一些患者 发生射血分数保留性心力衰竭（HFpEF）。因此，阐明潜在的分子 糖尿病性心肌病的发病机制至关重要。肥胖患者的心脏胰岛素 耐药性、II型糖尿病和HFpEF通常发展为低度炎症。促炎细胞因子 和趋化因子，包括TNF-α、IL-1 β、IL-6和MCP-1，在脂肪组织中产生，浸润 炎性细胞和局部细胞类型，包括内皮细胞和心肌细胞（CM）， 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 糖尿病性心肌病的发展。然而，哪些细胞类型在初始阶段产生细胞因子 糖尿病性心肌病的发病机制以及其潜在的发病机制还知之甚少。而且 与全身性炎症相比，局部机制的重要性仍有待澄清。我们 初步结果表明FFA通过一种依赖于PPAR-NF-κ B的信号通路激活CM中IL-6的产生。 这反过来又促进了糖尿病心肌病的发展。在这项研究中，我们将澄清 心肌细胞中过氧化物酶体增殖物激活受体β 1和白细胞介素6在高脂饮食引起心功能不全中作用 消耗和升高FFA刺激CM中IL-6的分子机制。我们的整体 假设：CM中的PPAR γ是FFA增加的传感器，其通过以下途径触发糖尿病性心肌病： 生产IL-6。血浆FFA的增加通过增加CM中IL-6的转录直接刺激CM中IL-6的转录。 PPAR β-NF-κ B B异二聚体与位于IL-6启动子中的NF-κ B B元件的结合。IL-6产生于 CMs作为一种自分泌/旁分泌因子诱发糖尿病心肌病。目标1：阐明 心脏内源性过氧化物酶体增殖物激活受体β 1和白细胞介素6介导糖尿病心肌病的初步发展。目标二： 阐明PPAR γ刺激CM中IL-6转录的分子机制。目标3：评估 抑制PPAR γ-NF-κ B B异二聚体的形成是否抑制了CM产生IL-6， HFD消耗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，我们将获得一个概念验证， PPAR γ-NF-κ B B异源二聚体是糖尿病心肌病治疗的新靶点.我们希望我们的研究 应该证明一种新的机制，刺激CM中IL-6的局部先天性产生， 介导糖尿病性心肌病的初始发展，这与许多患者高度相关， 肥胖和边缘代谢综合征。