Cardiolipin and linoleate metabolism in the failing heart: effects on mitochondri

衰竭心脏中的心磷脂和亚油酸代谢：对线粒体的影响

基本信息

批准号：
8058690
负责人：
ADAM J CHICCO
金额：
$ 18.1万
依托单位：
COLORADO STATE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-04-15 至 2013-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8058690
关键词：
Accounting Aging Anabolism Arachidonic Acids Cardiac Cardiac Myocytes Cardiolipins Cardiomyopathies Cardiovascular Diseases Development Dilated Cardiomyopathy Enzymes Fatty Acids Heart Heart Diseases Heart Research Heart failure Human Hypertrophy Insulin Resistance Label Laboratories Light Link Linoleic Acids Linolenic Acids Liver Mediating Membrane Metabolism Mitochondria Molecular Molecular Conformation Mus Myocardial Obesity Pathogenesis Pathologic Pathology Phenotype Phospholipids Play Polyunsaturated Fatty Acids Process Production Proteins Rattus Reactive Oxygen Species Reporting Research Respiration Respiratory physiology Rodent Model Role Small Interfering RNA Stress Transgenic Mice Unsaturated Fatty Acids Up-Regulation Ventricular Remodeling Work base diabetic cardiomyopathy heart cell improved linoleoyl-CoA desaturase mitochondrial dysfunction novel therapeutics overexpression pressure public health relevance uptake

项目摘要

DESCRIPTION (provided by applicant): Accumulating evidence indicates that mitochondrial dysfunction contributes to the pathogenesis and/or progression of heart failure by reducing the capacity and/or efficiency of myocardial respiration and increasing production of reactive oxygen species. However, the development of efficacious therapies targeting these perturbations has been limited by an incomplete understanding of their molecular basis. Studies by our laboratory and others indicate that alterations in the metabolism of polyunsaturated fatty acids (PUFAs) may play an important role in these phenomena during development of heart failure by leading to dramatic changes in the fatty acid composition of myocardial phospholipids, particularly cardiolipin (CL) a unique tetra-acyl mitochondrial phospholipid that provides essential support to proteins involved in mitochondrial respiration. CL is optimally functional in the mammalian heart when it contains four linoleic acid (18:2) acyl chains (18:24CL), a conformation generated by a molecular remodeling process requiring 18:2 as a substrate. Decreases in myocardial 18:24CL have been reported in several cardiac pathologies associated with mitochondrial dysfunction, including human dilated cardiomyopathy, and multiple rodent models of heart failure and diabetic cardiomyopathy. Interestingly, in all of these pathologies, decreases in 18:24CL can be accounted for largely by dramatic increases in CL species containing highly unsaturated fatty acid (HUFAs, chiefly, arachidonic acid (20:4) and/or DHA (22:6)), which parallel a global loss of 18:2 and accumulation of these HUFAs in the global myocardial phospholipid fatty acid pool. Recent studies in our laboratory indicate that this remodeling of myocardial phospholipids results from increased expression/activity of delta-6 desaturase (D6D) the rate- limiting enzyme in the biosynthesis of HUFAs from 18:2 and linolenic acid (18:3). Pharmacological inhibition of D6D in spontaneously hypertensive heart failure (SHHF) rats and obese/insulin resistant (ob) mice normalized the CL compositional profile, improved mitochondrial respiratory function, reduced mitochondrial ROS production, and decreased lipoxidative stress to levels near their respective healthy controls. The studies in this proposal will determine if upregulation D6D is sufficient to elicit the mitochondrial dysfunction and cardiac pathology with which it has been associated in these studies, and the extent to which cardiomyocyte D6D (as opposed to liver or "systemic" D6D activity) contributes to the desaturation of CL and membrane fatty acids in the failing heart. We will accomplish these aims by 1) examining the uptake and desaturation of 2H-labeled PUFAs into CL and other phospholipid species of cardiomyocytes isolated from failing and non-failing SHHF rats in the presence and absence of pharmacological or siRNA-mediated inhibition of D6D, and 2) by characterizing the cardiac mitochondrial phenotype of a transgenic mouse with global overexpression of D6D. These studies will shed new light on the mechanism and pathophysiological significance of a widely reported phenomenon that may contribute to the pathogenesis of several prevalent forms of myocardial disease. PUBLIC HEALTH RELEVANCE: Recent studies in our laboratory indicate that changes in the composition of fatty acids in the heart leads to pathologic changes in cardiac mitochondria, the 'powerhouses' of heart cells, that may contribute to the development and/or progression of heart failure. The studies in this proposal will elucidate the mechanisms and pathological importance of these phenomena in hopes of developing new therapeutic strategies for the management of heart disease.

描述（由申请人提供）：越来越多的证据表明，线粒体功能障碍通过降低心肌呼吸的能力和/或效率以及增加活性氧的产生而导致心力衰竭的发病机制和/或进展。然而，针对这些扰动的有效疗法的开发由于对其分子基础的不完全了解而受到限制。我们实验室和其他人的研究表明，多不饱和脂肪酸（PUFA）代谢的改变可能在心力衰竭发展过程中的这些现象中发挥重要作用，导致心肌磷脂的脂肪酸组成发生巨大变化，特别是心磷脂（CL））一种独特的四酰基线粒体磷脂，为参与线粒体呼吸的蛋白质提供必要的支持。当 CL 含有四个亚油酸 (18:2) 酰基链 (18:24CL)（一种由需要 18:2 作为底物的分子重塑过程产生的构象）时，CL 在哺乳动物心脏中具有最佳功能。据报道，在几种与线粒体功能障碍相关的心脏病理学中，心肌 18:24CL 降低，包括人类扩张型心肌病以及多种啮齿动物心力衰竭和糖尿病心肌病模型。有趣的是，在所有这些病理学中，18:24CL 的减少很大程度上是由于含有高度不饱和脂肪酸（HUFA，主要是花生四烯酸 (20:4) 和/或 DHA (22:6)）的 CL 种类急剧增加所致。），这与 18:2 的整体损失和这些 HUFA 在整体心肌磷脂脂肪酸池中的积累是平行的。我们实验室最近的研究表明，心肌磷脂的这种重塑是由于 delta-6 去饱和酶 (D6D) 表达/活性增加所致，D6D 是 18:2 和亚麻酸 (18:3) 的 HUFA 生物合成中的限速酶。在自发性高血压心力衰竭 (SHHF) 大鼠和肥胖/胰岛素抵抗 (ob) 小鼠中，D6D 的药理抑制作用使 CL 成分正常化，改善线粒体呼吸功能，减少线粒体 ROS 产生，并将脂氧化应激降低至接近各自健康对照的水平。本提案中的研究将确定 D6D 的上调是否足以引起这些研究中与之相关的线粒体功能障碍和心脏病理学，以及心肌细胞 D6D（相对于肝脏或“全身”D6D 活性）的贡献程度导致衰竭心脏中 CL 和膜脂肪酸的去饱和。我们将通过以下方式实现这些目标：1) 在存在和不存在药理学或 siRNA 介导的 D6D 抑制的情况下，检查从衰竭和非衰竭 SHHF 大鼠中分离出的 CL 和其他磷脂种类的心肌细胞中 2H 标记的 PUFA 的摄取和去饱和情况， 2) 通过表征全面过度表达 D6D 的转基因小鼠的心脏线粒体表型。这些研究将为广泛报道的现象的机制和病理生理学意义提供新的线索，这种现象可能导致几种流行形式的心肌疾病的发病机制。公共卫生相关性：我们实验室最近的研究表明，心脏中脂肪酸组成的变化会导致心脏线粒体（心脏细胞的“发电站”）发生病理变化，这可能会导致心力衰竭的发生和/或进展。该提案中的研究将阐明这些现象的机制和病理学重要性，希望开发新的心脏病治疗策略。