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剂

• 批准号: 10518319
• 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/10518319
• 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; 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.

项目概要 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，这些疾病 流行病比例上升并导致包括心力衰竭在内的不良后果。有一个共识是 腹部肥胖是代谢综合征发病机制的主要驱动力，具有严重的不良影响 对心血管危险因素的影响。人们越来越认识到脂肪组织功能障碍 脂肪因子失衡会影响肥胖人群的心脏病，但一个不太了解的机制是 心脏代谢和功能对全身代谢稳态的影响。事实上，人们知之甚少 将心脏功能障碍和全身代谢联系起来的因素。我对翻译有着长期的兴趣 心血管研究，之前的研究表明 GRK2 活性和表达升高 疾病早期并有助于进展。最近，我的实验室表明心脏限制表达 GRK2 (βARKnt) 的短氨基末端片段具有心脏保护作用。此外，虽然 GRK2 会产生负面影响 通过与胰岛素受体底物 1 (IRS1) 直接相互作用并磷酸化胰岛素信号传导， βARKnt 增强胰岛素信号通路的激活和线粒体效率。我们的初步数据 还表明 βARKnt 可以降低腹部脂肪含量并在治疗过程中保持全身胰岛素反应性 高脂肪饮食引起的肥胖。目前，我们发现了内源性GRK2和βARKnt的选择性相互作用 具有 160kDa (AS160) 的 Akt 底物。该蛋白质组数据的通路分析证实了 AS160/GRK2 链接 并涉及许多胰岛素信号调节因子。 AS160已被确定为之间的节点调节器 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已经 受到可用或选定模型的限制的阻碍。我们假设增强 AS160 信号传导 心肌细胞以保护心脏的方式提高其代谢灵活性，并将其转化为 对全身胰岛素反应性产生有益影响。目标 1 将探讨心脏的生理作用 AS160 在胰岛素刺激的 GLUT4 膜运输中及其对代谢物摄取的功能影响 和心脏中的线粒体呼吸。目标 2 将阐明心脏 AS160 调节因子的组成 使用交联/质谱法来可视化人体左侧的成分及其相互作用的复合物 患有或不患有糖尿病的心力衰竭患者的心室样本与小鼠模拟物相比 疾病。这些研究旨在填补我们关于心脏成分的知识空白。 AS160 调节复合体，它在心脏代谢应激过程中如何改变，它如何调节心肌细胞 代谢物利用，以及它是否会影响全身代谢性能。我们的整体 目标是更好地了解 AS160 在心肌细胞胰岛素中的调节和相关性 反应性以及它是否代表心脏代谢疾病的治疗靶点。