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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.