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（由申请人提供）：肥胖、2 型糖尿病 (T2DM) 和胰岛素抵抗是心力衰竭的独立危险因素。该提案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。还可能加速压力超负荷肥大时不利的左心室重塑，并且心肌细胞中胰岛素信号的遗传减少限制肥大重塑并减少压力超负荷时的细胞凋亡，从而保留左心室功能。高胰岛素血症通过促进 ß2ARGi 偏向信号传导和诱导磷酸二酯酶 (PDE4D) 使 ß-AR 介导的心肌收缩力刺激脱敏，这代表了一种将胰岛素抵抗、高胰岛素血症和左心室功能障碍联系起来的新机制。该提案将检验高胰岛素血症减弱的假设。通过两种不同的机制直接损害 AR 信号传导来降低左心室收缩力：(1) 增加2AR/Gi 偶联可抑制腺苷酸环化酶 (AC) 和 cAMP 的产生，以及 (2) 增加 PDE4D 的表达，从而增加 cAMP 的降解。这项多 PI 提案是 Evan Dale Abel（爱荷华大学）和 Yang 实验室的积极合作。 Kevin Fang（加州大学戴维斯分校）。我们综合了心肌胰岛素信号传导和心肌肾上腺素信号传导方面的专业知识，使用新型分子生物传感器来定义心肌细胞中的亚细胞肾上腺素能信号传导域和一系列具有干扰的 IR 或 βAR 信号传导的突变小鼠模型将在以下三个具体目标中解决这一假设：将定义 PDE4 诱导的分子机制和后果。假设：胰岛素信号通过 2AR-ERK 依赖的 PDE4 转录调节增加心脏 PDE4 水平以促进 cAMP 水解，从而降低 cAMP 水平。目标 2 (Abel)：将确定调节 IR-β2AR 信号传导可减轻肥胖相关左心室功能障碍的机制。假设：急性或慢性高胰岛素血症将通过促进心肌 βAR 信号传导而损害心肌 βAR 信号传导并降低收缩力或正性肌力储备。 cAMP 降解和这种串扰的遗传或药理学抑制将在高胰岛素状态下保持左心室功能。目标 3 (Abel) 将确定是否。 IR-2AR 串扰导致心力衰竭或胰岛素抵抗受试者的左心室功能障碍。假设：心力衰竭受试者的左心室或心房组织将揭示与 IR-2AR ERK 激活和 PDE4 诱导增加一致的分子特征。胰岛素抵抗受试者会对次最大运动表现出心率反应受损。这些研究将全面剖析限制 IR-AR 串扰的机制。胰岛素抵抗状态下的心肌收缩力，可能会导致治疗或预防患有胰岛素抵抗和代谢综合征的高危人群心力衰竭的新方法。