Cross-talk with the Insulin Receptor Attenuates Adrenergic Function within the He

与胰岛素受体的串扰减弱了He内的肾上腺素能功能

• 批准号: 8463028
• 负责人: David Cervantes
• 金额: $ 4.72万
• 依托单位: UNIVERSITY OF ILLINOIS AT URBANA-CHAMPAIGN
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-05-15 至 2014-05-14
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8463028
• 关键词: A kinase anchoring protein; Accounting; Acute; Adrenergic Agents; Adrenergic Receptor; Affect; Animals; Attenuated; Biological Models; Cardiac; Cardiac Myocytes; Cardiomyopathies; Catecholamines; Cell membrane; Chronic; Complex; Coronary Arteriosclerosis; Coupling; Cyclic AMP; Cyclic AMP-Dependent Protein Kinases; Cytosol; Data; Depressed mood; Diabetes Mellitus; Diffusion; Disease; Down-Regulation; Epidemic; Fluorescence Resonance Energy Transfer; Functional disorder; Genes; Heart; Heart failure; Hyperinsulinism; Hypertension; Imaging Techniques; Impairment; In Vitro; Insulin; Insulin Receptor; Isoproterenol; Measurement; Mediating; Modeling; Molecular; Mus; Muscle Cells; Myocardium; Non-Insulin-Dependent Diabetes Mellitus; Performance; Perfusion; Pertussis Toxin; Phosphorylation; Physiological; Population; Protein Isoforms; Proteins; Receptor Activation; Receptor Cross-Talk; Recombinants; Rest; Risk Factors; Signal Transduction; Signaling Protein; Time; Work; adenoviral-mediated; adrenergic; base; cellular imaging; desensitization; diabetic cardiomyopathy; diabetic patient; in vivo; inhibitor/antagonist; insulin signaling; mutant; novel therapeutics; phosphodiesterase IV; phospholamban; prevent; receptor; response; trafficking

DESCRIPTION (provided by applicant): Diabetes Mellitus is a growing epidemic, affecting 8% percent of population in the US. Type 2 diabetes mellitus, accounting for 90-95% of diabetes cases, is a well characterized risk factor for cardiomyopathy and heart failure. Diabetic Cardiomyopathy (DCM) is characterized by both systolic and diastolic dysfunction, resulting in decreased cardiac function, in the absence of coronary artery disease (CAD) and hypertension. Interestingly, DCM is associated with hyperinsulinemia and depressed adrenergic signaling leading to decreased contractility despite elevated catecholamine levels. The lack of CAD and hypertension in DCM, even in the presence of elevated catecholamines, suggests that hyperinsulinemia elicits direct cardiomyocyte insult, possibly by modulating adrenergic function. The consequence of concomitant insulin receptor (IR) and adrenergic receptor (AR) stimulation within the heart, however, remains unknown. Here, our major hypothesis is that insulin signaling attenuates the 2AR-induced elevation in cardiac performance in response to elevated catecholamines. Our preliminary data show that chronic insulin treatment impairs 2AR stimulation of cAMP/protein kinase A (PKA) signaling, PKA phosphorylation of phospholamban (PLN), and myocyte contraction rate response in cardiac myocytes. This inhibitory effect is mediated by both enhanced 2AR/Gi coupling and an increased expression of phosphodiesterase 4 (PDE4); together these contribute to a down-regulation of 2AR-induced cAMP signaling. The signaling mechanism underlying the cross-talk between IRs and 2ARs, as well as the physiological consequence, in the myocardium remains unknown. We hypothesize that decreased cardiac performance observed in DCM results, in part, from chronic insulin stimulation which impairs 2AR signaling via increased 2AR/Gi coupling and increased PDE4 expression. By combining our well-established model system based on myocytes isolated from 2AR gene deficient mice with our newly-developed FRET-based cell imaging techniques to analyze the dynamics of cAMP/PKA activities, we will determine the mechanism and consequence of 2AR/IR cross-talk in cardiomyocytes. The combination of functional myocyte contraction measurements and real-time measurement of 2AR-induced cAMP/PKA activities with recombinant adenoviral-mediated delivery of mutant signaling components allows for a unique yet powerful approach to uncover the mechanism underlying the functional integration of the insulin and 2AR signaling network. By elucidating the mechanism by which insulin attenuates adrenergic-mediated cardiac contractility both in vitro and in vivo, new therapeutic strategies may be developed to treat diabetic patients with heart failure.

描述（由申请人提供）：糖尿病是一种流行病，影响了美国8％的人口。 2型糖尿病，占糖尿病病例的90-95％，是心肌病和心力衰竭的危险因素。在没有冠状动脉疾病（CAD）和高血压的情况下，糖尿病心肌病（DCM）的特征是收缩和舒张功能障碍，导致心脏功能降低。有趣的是，DCM与高胰岛素血症和抑郁肾上腺素能信号有关，尽管儿茶酚胺水平升高，导致收缩力降低。即使在儿茶酚胺升高的情况下，DCM中缺乏CAD和高血压也表明高胰岛素血症会引起直接的心肌细胞损伤，这可能是通过调节肾上腺素能功能。然而，心脏内胰岛素受体（IR）和肾上腺素能受体（AR）刺激的结果仍然未知。在这里，我们的主要假设是胰岛素信号传导减弱了2AR诱导的心脏性能升高，以响应升高的儿茶酚胺。 我们的初步数据表明，慢性胰岛素治疗会损害2AR刺激CAMP/蛋白激酶A（PKA）信号传导，PKA磷酸化（PLN）（PLN）（PLN）（PLN）和心肌细胞中肌细胞的收缩率反应。这种抑制作用均通过增强的2AR/GI偶联和磷酸二酯酶4的表达增加（PDE4）介导。这些共同导致了2AR诱导的cAMP信号传导的下调。在心肌中，IRS和2ARS之间的串扰以及生理后果的信号传导机制仍然未知。 我们假设在DCM结果中观察到的心脏性能降低，部分原因是慢性胰岛素刺激通过增加的2AR/GI耦合而损害2AR信号传导并增加了PDE4表达。通过将基于从2AR基因缺陷小鼠分离的肌细胞与新开发的基于FRET的细胞成像技术分离的肌细胞相结合，以分析CAMP/PKA活动的动力学，我们将确定心肌细胞中2AR/IR串扰的机制和结果。功能性心肌收缩测量和2AR诱导的CAMP/PKA活性与重组腺病毒介导的突变体信号成分的递送的相结合，可以采用独特而强大的方法来揭示胰岛素和2AR信号网络功能整合的基础机制。通过阐明胰岛素在体外和体内减弱肾上腺素能介导的心脏收缩力的机制，可以开发出新的治疗策略来治疗心脏衰竭的糖尿病患者。