Targeting metabolic remodeling and mitochondrial dysfunction in the diabetic heart

针对糖尿病心脏的代谢重塑和线粒体功能障碍

• 批准号: 10490962
• 负责人: Tyler N Kambis
• 金额: $ 0.88万
• 依托单位: UNIVERSITY OF NEBRASKA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-02-01 至 2022-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10490962
• 关键词: 3-hydroxy-3-methylglutaryl-coenzyme A; Cardiac; Cardiac Myocytes; Cardiomyopathies; Cardiovascular Diseases; Carnitine; Carrier Proteins; Citric Acid Cycle; Coenzyme A; Crossbreeding; Data; Dependence; Diabetes Mellitus; Disease remission; Ectoderm; Electrophoretic Mobility Shift Assay; Enzymes; Fluorescence; Genetic Transcription; Glucose; Heart; Heart failure; Impairment; In Situ Hybridization; In Vitro; Individual; Insulin-Dependent Diabetes Mellitus; Ketone Bodies; Knowledge; Lipids; Measures; Membrane Potentials; Metabolic; Metabolism; MicroRNAs; Mitochondria; Molecular; Mus; Myocardial dysfunction; Myocardium; Myopathy; Neonatal; Parkin; Pathway interactions; Production; Quality Control; Respiration; Risk; Risk Factors; Role; Small Interfering RNA; Stress; Techniques; Testing; Therapeutic; Time; Tissues; Transferase; Transmission Electron Microscopy; Up-Regulation; base; cardioprotection; deep sequencing; design; diabetic; diabetic cardiomyopathy; early onset; experimental study; fatty acid metabolism; fatty acid oxidation; fatty acid-transport protein; glucose uptake; glycemic control; heart metabolism; improved; in silico; in vivo; inhibitor; ketogenesis; mitochondrial dysfunction; mitochondrial membrane; mouse model; novel; overexpression; preservation; prevent; protein expression; relating to nervous system; restoration; therapeutic candidate

Diabetes mellitus (DM) induces a cardiac muscle disorder known as diabetic cardiomyopathy (DMCM) that progresses to heart failure. A hallmark of DMCM is disrupted metabolism, resulting from increased dependency on fatty acid oxidation (FAO) for ATP production. Increased FAO results in mitochondrial stress and ultimately mitochondrial dysfunction, however the underlying molecular mechanisms are unclear. Ketogenesis is a fatty acid oxidation spillover pathway that contributes to mitochondrial damage via the rate limiting enzyme 3-Hydroxy-3-Methylglutaryl-CoA Synthase 2 (HMGCS2). Mitochondrial damage is further compounded by impaired mitophagy, the degradation of damaged mitochondria, in the DM heart. Furthermore, miR-133a, a highly abundant and cardioprotective miRNA, is downregulated in the DM heart. However, it is unclear how miR-133a regulates metabolic remodeling and mitochondrial damage in diabetic cardiomyopathy. My preliminary data shows that overexpression of miR-133a prevents mitochondrial lipid accumulation, upregulates fatty acid transport proteins, and downregulates HMGCS2 expression in the Type 1 DM (T1DM) heart. Moreover, miR-133a upregulated the mitophagy associated protein Parkin, plausibly by targeting Ectoderm Neural Cortex 1 (ENC1) - an inhibitor of mitophagy. Thus, we hypothesize that decreased fatty acid metabolism induces spillover activation of ketogenesis in the T1DM heart contributes to mitochondrial dysfunction, which is exacerbated by impaired mitophagy via upregulated ENC1 and ameliorated by increased expression of miR-133a in diabetic cardiomyopathy. I will examine whether ketogenesis is increased in the T1DM heart, and if miR-133a mitigates ketogenesis and restores mitophagy by formulating two specific Aims. Aim 1: To test the hypothesis that activation of ketogenesis leads to mitochondrial dysfunction in DMCM, which is mitigated in part by increased expression of miR-133a in the T1DM heart. Aim 2: To test the hypothesis that increased ENC1 impairs mitophagy in diabetic cardiomyopathy, which is ameliorated in part by upregulation of miR-133a in the T1DM heart. These studies will unravel a novel regulatory mechanism of ketogenesis and mitochondrial damage in DMCM and provide a miR-133a-based therapeutic approach to ameliorate cardiac metabolic derangement and mitochondrial dysfunction in DMCM.

糖尿病（DM）会诱发一种称为糖尿病性心肌病（DMCM）的心肌紊乱，并发展为心力衰竭。DMCM的一个特征是代谢紊乱，这是由于ATP生产对脂肪酸氧化（FAO）的依赖性增加所致。粮农组织增加导致线粒体应激并最终导致线粒体功能障碍，但潜在的分子机制尚不清楚。酮生是一种脂肪酸氧化溢出途径，通过限速酶3-羟基-3-甲基戊二酰辅酶a合成酶2 （HMGCS2）导致线粒体损伤。线粒体损伤进一步加剧了线粒体自噬受损，受损线粒体的降解，在糖尿病心脏。此外，miR-133a是一种高度丰富的心脏保护miRNA，在糖尿病心脏中下调。然而，目前尚不清楚miR-133a如何调节糖尿病心肌病的代谢重塑和线粒体损伤。我的初步数据显示，在1型DM （T1DM）心脏中，miR-133a的过表达可以阻止线粒体脂质积累，上调脂肪酸转运蛋白，下调HMGCS2的表达。此外，miR-133a上调线粒体自噬相关蛋白Parkin，可能是通过靶向外胚层神经皮层1 （Ectoderm Neural Cortex 1, ENC1）——一种线粒体自噬抑制剂。因此，我们假设，脂肪酸代谢的减少诱导了T1DM心脏中生酮的溢出激活，从而导致线粒体功能障碍，而线粒体功能障碍通过ENC1的上调而因线粒体自噬受损而加剧，并通过糖尿病心肌病中miR-133a的表达增加而改善。我将研究T1DM心脏中的生酮是否增加，以及miR-133a是否通过制定两个特定目的来减轻生酮和恢复线粒体自噬。目的1：验证激活生酮导致DMCM线粒体功能障碍的假设，这在一定程度上可以通过T1DM心脏中miR-133a的表达增加来缓解。目的2：验证ENC1升高会损害糖尿病心肌病的线粒体自噬的假设，这在一定程度上可以通过上调T1DM心脏中的miR-133a来改善。这些研究将揭示DMCM中生酮和线粒体损伤的新调控机制，并为改善DMCM中心脏代谢紊乱和线粒体功能障碍提供基于mir -133的治疗方法。