Cardiac Dysfunction in the Met Syndrome: Cross-talk between IR and bAR Signaling

描述(申请人提供)：肥胖、2型糖尿病(T2 DM)和胰岛素抵抗是心力衰竭的独立风险因素，心力衰竭影响到美国人口中迅速增长的一部分。这项建议的长期目标是了解在心力衰竭前和心力衰竭时将这些代谢紊乱和左心室(LV)功能障碍联系起来的机制。肥胖与胰岛素抵抗、高脂血症、糖耐量异常和高胰岛素血症有关。流行病学研究表明，高胰岛素血症是心力衰竭的独立危险因素。在人类和小鼠模型中，心脏可能通过胰岛素激活IRS1、PI3K和Akt信号的能力来保持其对胰岛素的敏感性，尽管其他器官如肝脏和骨骼肌存在胰岛素抵抗。这种高胰岛素血症也加速了压力超负荷肥厚时的不利左室重构，心肌细胞胰岛素信号的遗传减少限制了肥厚重构，减少了压力超负荷时的细胞凋亡，从而保护了左心功能。我们最近的研究表明，高胰岛素血症使�R介导的心肌收缩能力刺激变得不敏感，这代表了一种新的机制，将胰岛素抵抗、高胰岛素血症和左心功能不全联系在一起。因此，这项建议将侧重于这样一种假设，即高胰岛素血症可能通过直接损害�或�肾上腺素能(�)信号来减弱左心室收缩能力。具体地说，在高胰岛素血症状态下，心肌细胞胰岛素受体(IR)的激活通过两种不同的机制损害�信号：(1)增加�R/GI偶联，抑制腺苷环化酶和cAMP的产生；(2)增加PDE4D的表达，增加cAMP的降解。这一多PI提案反映了爱荷华大学的Evan Dale Abel和加州大学戴维斯分校的杨凯文·翔的实验室的积极合作。我们在心肌胰岛素信号转导和心肌肾上腺素能信号转导方面的专业知识将在以下两个特定目标中解决这一假设。目标1(向)。将通过检验以下假设来确定胰岛素损害心肌细胞�信号的分子机制：胰岛素信号通过含有�R、IR、IR和�K2的复合体增加GRK2R/GI偶联，从而抑制腺酰环化酶介导的cAMP的产生。胰岛素信号通过�R-ERK依赖的PDE4转录和蛋白质周转调节来提高心脏PDE4水平。目标2(亚伯)。将通过检验以下假设来确定�-IR在活体心脏中相互作用的生理后果：急性或慢性高胰岛素血症会损害心肌�信号并减少收缩或变力储备，肥胖、2型糖尿病和心力衰竭的高胰岛素血症会通过损害变力储备而加剧心功能障碍。通过使用新的分子生物传感器来确定心肌细胞中的亚细胞肾上腺素能信号域，以及一系列带有干扰的IR或�信号的突变小鼠模型，我们将剖析IR-�串扰在胰岛素抵抗状态下限制心肌收缩的机制。

DESCRIPTION (provided by applicant): Obesity, type 2 diabetes (T2DM) and insulin resistance are independent risk factors for heart failure, which affects a rapidly increasing segment of the US population. The long-term goal of this proposal is to understand the mechanisms linking these metabolic disorders and left ventricular (LV) dysfunction prior to and in concert with heart failure. Obesity is associated with insulin resistance, hyperlipidemia, glucose intolerance and hyperinsulinemia. Epidemiological studies suggest that hyperinsulinemia is an independent risk factor for heart failure. In humans and mouse models, the heart may retain its insulin sensitivity in terms of insulin's ability to activate IRS1, PI3K ad Akt signaling, despite insulin resistance in other organs such as the liver and skeletal muscle. This hyperinsulinemia also accelerates 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 �R-mediated stimulation of cardiac contractility, which represents a novel mechanism linking insulin resistance, hyperinsulinemia and LV dysfunction. This proposal, will therefore focus on the hypothesis that hyperinsulinemia might attenuate LV contractility by directly impairing �or �-adrenergic (�) signaling. Specifically, activation of cardiomyocyte insulin receptors (IR) in hyperinsulinemic states, impairs � signaling via two distinct mechanisms: (1) Increased �R/Gi coupling that inhibits adenylyl cyclase 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 will address this hypothesis in the following two specific aims. Aim 1 (Xiang). Will define the molecular mechanisms by which insulin impairs � signaling in cardiomyocytes by testing the following hypotheses: Insulin signaling increases �R/Gi coupling via a complex containing �R, IR, IRS, and GRK2 that inhibits adenylyl cyclase-mediated cAMP generation. Insulin signaling enhances cardiac PDE4 levels via �R-ERK dependent modulation of PDE4 transcription and protein turnover. Aim 2 (Abel). Will determine the physiological consequences of �-IR interactions in hearts in vivo by testing the hypotheses that: Acute or chronic hyperinsulinemia will impair myocardial � signaling and reduce contractility or inotropic reserve and that hyperinsulinemia in obesity, T2DM and heart failure will exacerbate cardiac dysfunction by impairing inotropic reserve. By using novel molecular biosensors to define subcellular adrenergic signaling domains in cardiomyocytes and a comprehensive array of mutant mouse models with perturbed IR or � signaling, we will dissect the mechanism for IR-� crosstalk that limits myocardial contractility in insulin resistant states.