AS160 as a nodal regulator of the cardiac response to metabolic stress

AS160 作为心脏对代谢应激反应的节点调节器

• 批准号: 10674917
• 负责人: Sarah Marie Bass
• 金额: $ 56.32万
• 依托单位: CLEVELAND CLINIC LERNER COM-CWRU
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-08-01 至 2027-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10674917
• 关键词: ADRBK1 gene; Adipocytes; Adipose tissue; Adult; Adverse effects; Affect; American; Binding; Biological Markers; Biology; Body mass index; Cardiac; Cardiac Myocytes; Cardiometabolic Disease; Cardiovascular system; Cause of Death; Central obesity; Chronic; Co-Immunoprecipitations; Complex; Consensus; Country; Cues; Data; Diabetes Mellitus; Diet; Disease; Epidemic; Functional disorder; G protein coupled receptor kinase; GLUT 4 protein; Goals; Heart; Heart Diseases; Heart failure; High Fat Diet; Homeostasis; Human; Immunoprecipitation; Insulin; Insulin Resistance; Insulin Signaling Pathway; Intervention Studies; Investigation; Knock-in; Knock-out; Knowledge; Left; Length; Life Style; Link; Mass Spectrum Analysis; Mediating; Membrane; Metabolic; Metabolic Diseases; Metabolic stress; Metabolic syndrome; Metabolism; Mitochondria; Modeling; Mus; Mutation; Myocardial dysfunction; N-terminal; Nodal; Non-Insulin-Dependent Diabetes Mellitus; Obesity; Organ; Outcome; Pathogenesis; Pathway Analysis; Pathway interactions; Patients; Peptides; Performance; Phenotype; Phosphorylation; Phosphotransferases; Physiological; Protein Inhibition; Proteins; Proteomics; Proto-Oncogene Proteins c-akt; Regulation; Research; Respiration; Role; Sampling; Severity of illness; Signal Transduction; Skeletal Muscle; Stress; Stroke; Tertiary Protein Structure; Therapeutic Intervention; Tissue Sample; Translating; United States; Ventricular; Vesicle; Visualization; Woman; Work; abdominal fat; adipokines; atherosclerosis risk; cardiometabolism; cardioprotection; cardiovascular disorder risk; cardiovascular risk factor; crosslink; diet-induced obesity; driving force; flexibility; genetic risk factor; glucose uptake; heart function; heart metabolism; improved; inhibitor; insight; insulin receptor substrate 1 protein; insulin regulation; insulin sensitivity; insulin signaling; interest; knock-down; men; mortality; mouse model; negative affect; novel strategies; novel therapeutic intervention; obese person; preservation; pressure; recruit; response; small molecule; systemic inflammatory response; targeted treatment; therapeutic target; trafficking; uptake

PROJECT SUMMARY Heart disease is the leading cause of death for both men and women in the United States. Cardiovascular mortality rates positively correlate with the presence of diabetes, obesity and metabolic syndrome, which are rising in epidemic proportions and leading to poor outcomes including heart failure. There is a consensus that abdominal obesity is a major driving force in the pathogenesis of metabolic syndrome, with severe adverse effects on cardiovascular risk factors. In the midst of a growing recognition of how adipose tissue dysfunction and adipokine imbalance affect cardiac disease in the obese population, a less-well understood mechanism is the effect of cardiac metabolism and function on systemic metabolic homeostasis. In fact, little is known about the factors that link cardiac dysfunction and systemic metabolism. I have a long-standing interest in translational cardiovascular research, with previous investigations showing that elevated GRK2 activity and expression occurs early in disease and contributes to progression. Recently, my lab has shown that cardiac restricted expression of a short, amino terminal fragment of GRK2 (βARKnt) is cardioprotective. Further, while GRK2 negatively affects insulin signaling through a direct interaction with and phosphorylation of insulin receptor substrate-1 (IRS1), βARKnt enhances activation of the insulin signaling pathway and mitochondrial efficiency. Our preliminary data also show that βARKnt reduces abdominal fat content and preserves systemic insulin responsiveness during high fat diet-induced obesity. Currently, we discovered selective interactions of endogenous GRK2 and βARKnt with Akt substrate of 160kDa (AS160). Pathway analysis of this proteomic data confirmed an AS160/GRK2 link and involved numerous regulators of insulin signaling. AS160 has been identified as nodal regulator between insulin signaling and glucose uptake, but research into its physiological role in cardiomyocyte metabolism has been hampered by limitations of available or selected models. We hypothesize that enhancing AS160 signaling in cardiomyocytes improves their metabolic flexibility in a cardioprotective manner and translates these to beneficial effects on systemic insulin responsiveness. Aim 1 will interrogate the physiological role of cardiac AS160 in insulin-stimulated GLUT4 membrane trafficking and the functional consequences for metabolite uptake and mitochondrial respiration in the heart. Aim 2 will elucidate the composition of the cardiac AS160 regulatory complex using cross-linking/mass spectrometry to visualize the components and their interactions in human left ventricular samples from patients with heart failure with or without diabetes compared to murine mimics of disease. These studies seek to fill important gaps in our knowledge regarding the composition of the cardiac AS160 regulatory complex, how it is altered during cardiometabolic stress, how it regulates cardiomyocyte metabolite utilization, and whether it translates this to influencing systemic metabolic performance. Our overall goal is to gain a better understanding of the regulation and relevance of AS160 in cardiomyocyte insulin- responsiveness and whether it represents a therapeutic target for cardiometabolic disease.

项目摘要 心脏病是美国男性和女性死亡的主要原因。心血管 死亡率与糖尿病、肥胖症和代谢综合征的存在呈正相关， 流行比例上升，导致包括心力衰竭在内的不良结局。有一个共识， 腹型肥胖是代谢综合征发病机制的主要驱动力， 对心血管危险因素的影响。在越来越多的人认识到脂肪组织功能障碍 和脂肪因子失衡影响肥胖人群的心脏疾病，一个不太清楚的机制是 心脏代谢和功能对全身代谢稳态的影响。事实上，我们对 心脏功能障碍和全身代谢之间的联系。我对翻译有着长期的兴趣 心血管研究，先前的研究表明GRK 2活性和表达升高， 在疾病的早期，有助于疾病的发展。最近，我的实验室发现心脏限制性表达 GRK 2的氨基末端短片段（βARKnt）具有心脏保护作用。此外，虽然GRK 2负面影响 通过与胰岛素受体底物-1（IRS 1）的直接相互作用和磷酸化的胰岛素信号传导， βARKnt增强胰岛素信号通路的活化和线粒体效率。我们的初步数据 还表明，βARKnt减少腹部脂肪含量，并保持全身胰岛素反应性， 高脂肪饮食引起的肥胖。目前，我们发现内源性GRK 2和βARKnt的选择性相互作用， Akt底物分子量为160 kDa（AS 160）。对这些蛋白质组数据的通路分析证实了AS 160/GRK 2的连接 并涉及许多胰岛素信号调节剂。AS 160已被确定为节点调节器， 胰岛素信号传导和葡萄糖摄取，但对其在心肌细胞代谢中的生理作用的研究 受到现有或选定模型的限制。我们假设增强AS 160信号传导 在心肌细胞中，以心脏保护的方式改善其代谢灵活性，并将其转化为 对全身胰岛素反应性的有益作用。目的1将探讨心脏的生理作用 胰岛素刺激的GLUT 4膜运输中的AS 160和代谢物摄取的功能后果 以及心脏中的线粒体呼吸。目的2将阐明心脏AS 160调节蛋白的组成， 复杂的使用交联/质谱法可视化的成分和它们的相互作用，在人类左 来自患有或不患有糖尿病的心力衰竭的患者的心室样品与 疾病这些研究试图填补我们关于心脏组成的知识中的重要空白。 AS 160调节复合物，在心脏代谢应激期间如何改变，如何调节心肌细胞 代谢物利用率，以及是否将其转化为影响全身代谢性能。我们的整体 目的是更好地了解AS 160在心肌细胞胰岛素-β 2受体中的调节和相关性。 反应性以及它是否代表心脏代谢疾病的治疗靶点。