Insulin Inhibition of beta-AR Signaling in the Myocardium

 说明(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危险因素。这项建议的长期目标是了解这些人群中高胰岛素血症和心功能不全之间的关系。高胰岛素血症也可能加速压力超负荷肥厚时不利的左室重构，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，高胰岛素血症通过促进2Argi偏向的信号转导和诱导磷酸二酯酶(PDE4D)而使ç-AR介导的心肌收缩能力的刺激变得不敏感，这代表了胰岛素抵抗、高胰岛素血症和左心功能障碍之间的新机制。高胰岛素血症通过两种不同的机制直接损害AR信号，从而减弱左心室收缩功能的假说：(1)增加-2AR/GI偶联，抑制腺苷环化酶(AC)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和心肌肾上腺素能信号方面的专业知识结合在一起，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域，以及一系列具有干扰IR或βAR信号的突变小鼠模型，将在以下三个具体目标中解决这一假设。目标1(向)：将确定PDE4诱导对慢性高胰岛素血症的反应的分子机制和后果。假设：胰岛素信号通过2AR-ERK依赖的PDE4转录和蛋白周转调节cAMP水解酶的心脏PDE4水平来降低cAMP水平。目的2(ABEL)：将确定IR--2AR信号的调节可以减轻肥胖相关的左心功能障碍的机制。假设：急性或慢性高胰岛素血症将通过促进cAMP降解而损害心肌βAR信号，降低收缩或变力储备，而基因或药物抑制这一串扰将在高胰岛素状态下保护左心功能。目标3(亚伯)。将确定IR-2AR串扰是否导致心力衰竭或胰岛素抵抗受试者左心功能不全。假设：心力衰竭患者的左心室或心房组织将显示出与IR--2AR ERK活性增加和PDE4诱导一致的分子特征，胰岛素抵抗患者将对次极限运动表现出心率减慢的反应。这些研究将全面剖析IR-AR串扰在胰岛素抵抗状态下限制心肌收缩能力的机制，并可能导致在患有胰岛素抵抗和代谢综合征的高危人群中治疗或预防心力衰竭的新方法。

 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.