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

• 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
• 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

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，增加活性氧的产生，从而参与心力衰竭的发病和/或进展。然而，针对这些干扰的有效治疗方法的开发一直受到对其分子基础的不完全了解的限制。本实验室等人的研究表明，多不饱和脂肪酸(PUFAs)代谢的改变可能通过导致心肌磷脂，特别是心磷脂(CL)的脂肪酸组成的急剧变化，在心力衰竭的发展过程中发挥重要作用。心磷脂(CL)是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)时，CL在哺乳动物心脏中具有最佳功能，亚油酸是一种需要18：2为底物的分子重塑过程产生的构象。据报道，在与线粒体功能障碍相关的几种心脏病变中，心肌18：24CL降低，包括人类扩张型心肌病，以及心力衰竭和糖尿病心肌病的多种啮齿动物模型。有趣的是，在所有这些病理中，18：24CL的减少在很大程度上可以解释为含有高度不饱和脂肪酸(HUFAs，主要是花生四烯酸(20：4)和/或DHA(22：6))的CL种类急剧增加，这与18：2的全球损失和这些HUFA在全球心肌磷脂脂肪酸池中的积累相平行。我们实验室最近的研究表明，心肌磷脂的这种重构是由于β-6去饱和酶(D6D)的表达/活性增加所致，D6D是HUFAs生物合成中的限速酶，从18：2到亚麻酸(18：3)。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到接近各自健康对照的水平。这项建议中的研究将确定在这些研究中，上调D6D是否足以引起线粒体功能障碍和心脏病理，以及心肌细胞D6D(相对于肝脏或“全身性”D6D活动)在多大程度上有助于衰竭心脏CL和膜脂肪酸的去饱和。我们将通过1)检测在药物或siRNA介导的D6D抑制存在和不存在的情况下，2H标记的PUFAs在CL和其他磷脂种类的SHHF大鼠心肌细胞中的摄取和去饱和情况，以及2)通过鉴定D6D全球过表达的转基因小鼠的心肌线粒体表型。这些研究将为一种被广泛报道的现象的机制和病理生理学意义提供新的线索，这种现象可能有助于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的病理变化，这可能有助于心力衰竭的发展和/或进展。这项提案中的研究将阐明这些现象的机制和病理意义，希望为心脏病的管理开发新的治疗策略。