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）：积累的证据表明，线粒体功能障碍通过降低心肌呼吸的能力和/或效率来促进心力衰竭的发病机理和/或进展，并增加反应性氧物种的产生。但是，针对这些扰动的有效疗法的发展受到对它们的分子基础的不完全理解的限制。我们的实验室和其他人的研究表明，多不饱和脂肪酸（PUFAS）的代谢变化可能在这些现象中通过导致心力衰竭发展而在这些现象中起重要作用呼吸。当哺乳动物心脏中包含四个亚油酸（18：2）酰基链（18：24Cl）时，CL在哺乳动物心脏中的功能最佳，这是由分子重塑过程产生的构象，需要18：2作为底物。在与线粒体功能障碍相关的几种心脏病理中，心肌18：24CL的降低，包括人体扩张的心肌病，以及多种心力衰竭和糖尿病心肌病的啮齿动物模型。有趣的是，在所有这些病理中，在18：24Cl中的下降很大程度上是由于含有高度不饱和脂肪酸的Cl物种的急剧增加（HUFAS，主要是Arachidonic Acid（20：4）和/或DHA（22：6）），这与这些HUFAS的全球含量相似，并在全球范围内造成了全球含量的损失。我们实验室中的最新研究表明，心肌磷脂的重塑是由于增长量增加了三角中6D（D6D）的表达/活性增加了HUFA的生物合成速率酶从18：2和亚麻酸酸（18：3）（18：3）。 D6D在自发性高血压心力衰竭（SHHF）大鼠和肥胖/胰岛素耐药（OB）小鼠中对D6D的药理抑制作用使CL成分概况归一化，线粒体呼吸功能改善，线粒体ROS产生降低，降低了脂氧化压力，减少了脂氧化压力，可减少其接近其健康的健康对照水平。该提案中的研究将确定上调D6D是否足以引起与这些研究相关的线粒体功能障碍和心脏病理学，以及心肌细胞D6D的程度（与肝或“全身” D6D活性相反）有助于CL和杂膜脂肪酸的症状。我们将通过1）通过1）检查2H标记的PUFA在CL和其他磷脂物种中的吸收和去饱和度，这些心肌细胞因在存在和不存在药理学或缺乏药理学或SirNA介导的d6D抑制作用的情况下，并通过d6d的全球延伸而导致的鼠标米牛油剂表征过多的药理学或siRNA介导的过度疾病，从失败和未偿还的SHHF大鼠中分离出来的心肌细胞，并没有。 D6D。这些研究将为广泛报道的现象的机制和病理生理意义提供新的启示，该现象可能有助于几种流行形式的心肌疾病的发病机理。公共卫生相关性：我们实验室的最新研究表明，心脏中脂肪酸组成的变化会导致心脏线粒体的病理变化，即心脏细胞的“动力室”，这可能有助于心脏衰竭的发展和/或进展。该提案中的研究将阐明这些现象的机制和病理重要性，以期为治疗心脏病的治疗发展新的治疗策略。