Insulin Inhibition of beta-AR Signaling in the Myocardium

胰岛素对心肌 β-AR 信号传导的抑制

基本信息

批准号：
9036439
负责人：
E Dale Abel
金额：
$ 59.46万
依托单位：
UNIVERSITY OF IOWA
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-04-01 至 2019-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9036439
关键词：
ADRBK1 gene Acute Address Adenylate Cyclase Adrenergic Agents Animals Apoptosis Attenuated Biopsy Biosensor California Cardiac Cardiac Myocytes Cardiomyopathies Chronic Clinical Trials Collaborations Coupling Cyclic AMP Cyclic AMP-Dependent Protein Kinases Diabetes Mellitus Epidemiologic Studies Exercise Exhibits Fatty acid glycerol esters Functional disorder Genetic Genetic Transcription Goals Health Heart Heart Atrium Heart Rate Heart failure Human Hydrolysis Hyperinsulinism Hypertrophy IRS1 gene Impairment In Vitro Insulin Insulin Receptor Insulin Resistance Iowa Journals Knock-out Laboratories Lead Left Left Ventricular Dysfunction Left Ventricular Function Left Ventricular Remodeling Link Mediating Metabolic Control Metabolic syndrome Modeling Molecular Molecular Profiling Mus Muscle Cells Myocardial Myocardial dysfunction Myocardium Non-Insulin-Dependent Diabetes Mellitus Obesity Phosphorylation Population Prevalence Prevention Production Protein Isoforms Protocols documentation Publishing Randomized Receptor Signaling Risk Factors Role Signal Pathway Signal Transduction Testing Tissues United States Universities Ventricular Ventricular Remodeling Weight Yang auricular appendage constriction feeding glucose uptake high risk insulin sensitivity insulin signaling left ventricular assist device mortality mouse model mutant mutant mouse model novel novel strategies phosphodiesterase IV phospholamban phosphoric diester hydrolase pressure prevent protein degradation receptor response trafficking

项目摘要

DESCRIPTION (provided by applicant): Obesity, type 2 diabetes (T2DM), and insulin resistance are independent risk factors for heart failure. The long- term goal of this proposal is to understand the relationship between hyperinsulinemia and cardiac dysfunction in these populations. Hyperinsulinemia may also accelerate adverse LV remodeling in pressure overload hypertrophy and genetic reduction of insulin signaling in cardiomyocytes limits hypertrophic remodeling and reduces apoptosis in pressure overload, thereby preserving LV function. Our recent studies reveal that hyperinsulinemia desensitizes ß-AR-mediated stimulation of cardiac contractility by promoting ß2ARGi-biased signaling and by inducing the phosphodiesterase (PDE4D), which represents a novel mechanism linking insulin resistance, hyperinsulinemia and LV dysfunction. This proposal will test the hypothesis that hyperinsulinemia attenuates LV contractility by directly impairing AR signaling via two distinct mechanisms: (1) Increased 2AR/Gi coupling that inhibits adenylyl cyclase (AC) and cAMP production, and (2) Increased expression of PDE4D that increases cAMP degradation. This multi PI proposal reflects an active collaboration by the laboratories of Evan Dale Abel (University of Iowa) and Yang Kevin Xiang (University of California -Davis). Our combined expertise in myocardial insulin signaling and myocardial adrenergic signaling, using novel molecular biosensors to define subcellular adrenergic signaling domains in cardiomyocytes and a comprehensive array of mutant mouse models with perturbed IR or βAR signaling, will address this hypothesis in the following three specific aims. Aim 1 (Xiang): Will define the molecular mechanisms for and consequences of PDE4 induction in response to chronic hyperinsulinemia. Hypothesis: Insulin signaling reduces cAMP levels by increasing cardiac PDE4 levels for cAMP hydrolysis via 2AR-ERK dependent modulation of PDE4 transcription and protein turnover. Aim 2 (Abel): Will determine the mechanisms by which modulation of IR-2AR signaling may attenuate obesity associated LV dysfunction. Hypothesis: Acute or chronic hyperinsulinemia will impair myocardial βAR signaling and reduce contractility or inotropic reserve by promoting cAMP degradation and genetic or pharmacological inhibition of this crosstalk will preserve LV function in hyperinsulinemic states. Aim 3 (Abel). Will determine if IR-2AR crosstalk contributes to LV dysfunction in heart failue or in subjects with insulin resistance. Hypothesis: LV or atrial tissue from subjects with heart failure will reveal molecular signatures consistent with increased IR-2AR ERK activation and PDE4 induction, and insulin resistant subjects will exhibit impaired heart rate responses to sub-maximal exercise. These studies will comprehensively dissect the mechanism for IR-AR crosstalk that limits myocardial contractility in insulin resistant states, and may lead to novel approaches for treating or preventing heart failure in the high risk population with insulin resistance and the metabolic syndrome.

描述（适用提供）：肥胖症，2型糖尿病（T2DM）和胰岛素抵抗是心力衰竭的独立危险因素。该提议的长期目标是了解这些人群中高胰岛素血症和心脏功能障碍之间的关系。高胰岛素血症还可能加速肌肉超负荷肥大中的不良LV重塑，心肌细胞中胰岛素信号传导的遗传减少限制了肥大的重塑，并降低了压力过载中的凋亡，从而保留LV功能。我们最近的研究表明，高胰岛素血症通过促进β2ARGI偏见的信号传导和诱导磷酸二酯酶（PDE4D）脱敏心脏收缩性刺激，这代表了连接胰岛素抵抗的新机制，该机制是胰岛素抵抗，高胰岛素血症和LV功能障碍。该提案将检验以下假设：高胰岛素血症通过两种不同的机制直接损害AR信号来减轻LV的收缩力：（1）增加2AR/GI偶联，从而抑制腺苷酸环化酶（AC）和CAMP产生，以及（2）PDE4D的表达增加，从而增加了CAMP降级。该多PI提案反映了埃文·戴尔·阿贝尔（Evan Dale Abel）（爱荷华大学）和杨·凯文·徐（Yang Kevin Xiang）（加利福尼亚大学 - 达维斯大学）实验室的积极合作。我们使用新型的分子生物传感器来定义心肌细胞中的亚细胞肾上腺素信号传导域，并在以下三个特定的三个特定的目标中解决这一假设，我们将在心肌胰岛素信号传导和心肌肾上腺素信号传导方面的组合专业知识，并使用扰动的IR或βAR信号来定义突变小鼠模型中的全面小鼠模型，将在以下三个特定的特定目标中解决此假设。 AIM 1（Xiang）：将定义PDE4诱导对慢性高胰岛素血症的分子机制和后果。假设：胰岛素信号通过通过2AR-ERK依赖PDE4转录和蛋白质更新的cAMP水解的心脏PDE4水平来降低cAMP水平。 AIM 2（ABEL）：将确定IR-2AR信号调节可能减弱肥胖相关的LV功能障碍的机制。假设：急性或慢性高胰岛素血症会损害心肌β信号传导，并通过促进营地降解以及对这种串扰的遗传学或药理抑制来降低收缩性或肌力储备，将在高胰岛素状态下保留LV功能。目标3（亚伯）。将确定IR-2AR串扰是否有助于心脏失败或具有胰岛素抵抗的受试者的LV功能障碍。假设：来自心力衰竭受试者的LV或心房组织将揭示与IR-2ARERK激活和PDE4诱导增加的分子特征，并且抗胰岛素耐药受试者将暴露对亚最大运动的心率影响。这些研究将全面剖析IR-AR串扰的机制，该机制限制了胰岛素抵抗状态的心肌收缩性，并可能导致新的方法治疗或预防具有胰岛素抵抗和代谢综合征的高风险人群的心力衰竭。