Membrane-Mediated Alterations in Diabetes

糖尿病中膜介导的改变

• 批准号: 7895070
• 负责人: RICHARD W GROSS
• 金额: $ 217.36万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1997
• 资助国家: 美国
• 起止时间: 1997-09-01 至 2013-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7895070
• 关键词: Acyl Coenzyme A; Adverse effects; Atherosclerosis; Biochemical; Bioenergetics; Blood Vessels; CD36 gene; Calcium; Cardiac; Cardiac Myocytes; Cardiolipins; Characteristics; Chronic; Complex; Diabetes Mellitus; Disease; Fatty Acids; Foundations; Functional disorder; Genetic Transcription; Glucose; Insulin; Lead; Lipids; Mediating; Membrane; Metabolic; Mitochondria; Molecular; Morbidity - disease rate; Myocardial; Myocardial Ischemia; Myocardium; Myopathy; Pathologic; Phospholipase; Phosphorylation; Physiological; Predisposition; Proteomics; Reliance; Research; Research Personnel; Role; Signal Transduction; Technology; Translations; diabetic; diabetic cardiomyopathy; diabetic patient; fatty acid transport; feeding; flexibility; hemodynamics; insulin signaling; lipid metabolism; metabolomics; mitochondrial dysfunction; mortality; oxidized lipid; prevent; programs; trafficking; ventricular hypertrophy

DESCRIPTION (provided by applicant): Diabetic cardiomyopathy is a complex disorder that results from maladaptive changes in cardiac lipid metabolism in the diabetic state. The prolonged and nearly exclusive reliance on fatty acid substrate to fuel contractile function in myocardium ultimately leads to an overt metabolic myopathy that is characterized clinically by the presence of diastolic dysfunction, ventricular hypertrophy and bioenergetic inefficiency that collectively increase the morbidity and mortality in diabetic patients. Diabetic patients are subject not only to the aggressive vascular atherosclerosis characteristic of the diabetic state, but are also predisposed to the increased adverse effects of myocardial ischemia on metabolically compromised myocardium. The unifying hypothesis of the program project is that the excessive utilization of fatty acid substrate to fuel hemodynamic function at the expense of glucose in diabetic myocardium results in a metabolic imbalance that leads to the in appropriate activation of phospholipases precipitating membrane dysfunction. These alterations in membrane function compromise the bioenergetic efficiency and metabolic flexibility of diabetic myocardium and result in the increased susceptibility of diabetic myocardium to ischemic damage. The chronic excessive use of fatty acids results in the accumulation of toxic lipid metabolites such as acyl-CoA that serve dual roles in both cardiac bioenergetics and in cardiac myocyte signaling. Accumulation of acyl-CoA leads to the activation of intracellular calcium independent phospholipases (iPLA2s) (Project 1) that compromise membrane function and lead to alterations in mitochondrial bioenergetic efficiency through changes in cardiolipin content and molecular species composition (Project 2). Moreover, the chronic and excessive utilization of CD36 to facilitate fatty acid transport and trafficking ultimately leads to dysfunctional changes in CD36 signaling functions (Project 3). This distortion is propagated by chronic decreased insulin signaling in diabetic myocardium leading to decreased Akt signaling (Project 4) that has multiple effects on myocardium including the decreased phosphorylation of FOXO1 preventing physiologic insulin-mediated suppression of CD36 transcription and translation. The prolonged activation of phospholipases and CD36 in the diabetic state alters membrane function, fatty acid transport and trafficking that propagates the metabolic myopathy and altered cellular signaling in diabetic myocardium. Ultimately, mitochondrial dysfunction leads to a decrease in the ability to oxidize lipids efficiently promoting a feed forward cycle of cardiac dysfunction. The proposed research extends original discoveries made by Program investigators that are fundamental to the biochemical and pathologic sequelae of the diabetic state. The program provides a highly synergistic and interactive foundation through the integrated scientific themes of the component projects that are efficiently interfaced with the enabling technologies of lipidomics, proteomics. metabolomics and multiparametric physiologic assessments of myocardial function.

描述（由申请人提供）：糖尿病心肌病是一种复杂的疾病，是由糖尿病状态下心脏脂质代谢的适应不良变化引起的。长期且几乎完全依赖脂肪酸底物来促进心肌收缩功能，最终导致明显的代谢性肌病，其临床特征为存在舒张功能障碍、心室肥大和生物能低效，这些共同增加了糖尿病患者的发病率和死亡率。糖尿病患者不仅遭受糖尿病状态特有的侵袭性血管动脉粥样硬化，而且还容易遭受心肌缺血对代谢受损心肌的增加的不利影响。该计划项目的统一假设是，糖尿病心肌中过度利用脂肪酸底物以牺牲葡萄糖为代价来促进血流动力学功能，会导致代谢失衡，从而导致磷脂酶的不适当激活，从而导致膜功能障碍。这些膜功能的改变损害了糖尿病心肌的生物能效率和代谢灵活性，并导致糖尿病心肌对缺血性损伤的易感性增加。长期过量使用脂肪酸会导致有毒脂质代谢物（例如酰基辅酶A）的积累，酰基辅酶A在心脏生物能学和心肌细胞信号传导中发挥双重作用。酰基辅酶 A 的积累会导致细胞内钙非依赖性磷脂酶 (iPLA2) 的激活（项目 1），从而损害膜功能，并通过心磷脂含量和分子种类组成的变化导致线粒体生物能效率的改变（项目 2）。此外，长期过度利用 CD36 来促进脂肪酸转运和贩运最终会导致 CD36 信号传导功能发生功能失调（项目 3）。这种扭曲是通过糖尿病心肌中胰岛素信号传导的长期减少而传播的，导致 Akt 信号传导减少（项目 4），这对心肌有多种影响，包括 FOXO1 磷酸化的减少，防止生理性胰岛素介导的 CD36 转录和翻译抑制。糖尿病状态下磷脂酶和 CD36 的长期激活会改变膜功能、脂肪酸运输和运输，从而传播代谢性肌病并改变糖尿病心肌中的细胞信号传导。最终，线粒体功能障碍导致有效氧化脂质的能力下降，从而促进心脏功能障碍的前馈循环。拟议的研究扩展了项目研究人员的原始发现，这些发现对于糖尿病状态的生化和病理后遗症至关重要。该计划通过各组成项目的综合科学主题提供了高度协同和互动的基础，这些主题与脂质组学、蛋白质组学的支持技术有效结合。心肌功能的代谢组学和多参数生理评估。