Effects of Dietary Fat on Contractile and Mitochondrial Function in Heart Failure

膳食脂肪对心力衰竭患者收缩和线粒体功能的影响

• 批准号: 7416666
• 负责人: MARGARET P CHANDLER
• 金额: $ 37.5万
• 依托单位: CASE WESTERN RESERVE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-05-15 至 2011-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7416666
• 关键词: Accounting; Adipose tissue; Agonist; Animals; Apoptosis; Apoptotic; Atrial Natriuretic Factor; Biogenesis; Blood Vessels; CD36 gene; Cardiac; Cardiac Myocytes; Cardiomyopathies; Carnitine; Carnitine O-Palmitoyltransferase; Cell Death; Cells; Ceramides; Cessation of life; Chronic; Clinical; Complex; Condition; Coronary artery; Development; Diabetes Mellitus; Diet; Dietary Fats; Eating; Electron Transport; Elevation; Enzymes; Exposure to; Failure; Fat-Restricted Diet; Fatty Acids; Fatty acid glycerol esters; Functional disorder; Gene Expression; Genes; Genetic Transcription; Goals; Grant; Growth; Heart; Heart Diseases; Heart failure; Human; Hypertension; Hypertrophy; In Vitro; Individual; Insulin Resistance; Investigation; Laboratories; Lead; Left; Left Ventricular Hypertrophy; Ligation; Link; Lipids; Mediating; Mediator of activation protein; Messenger RNA; Metabolic; Metabolic Pathway; Mitochondria; Modeling; Modification; Myocardial; Myocardial Infarction; Myocardial tissue; Nature; Obesity; Operative Surgical Procedures; Oxidative Phosphorylation; PPAR alpha; PPAR gamma; Palmitates; Pathologic; Pathology; Pathway interactions; Peroxisome Proliferator-Activated Receptors; Personal Satisfaction; Physiology; Play; Polyunsaturated Fatty Acids; Post-Translational Protein Processing; Rate; Rattus; Research Personnel; Respiration; Rest; Role; Saturated Fatty Acids; Stress; Time; Transcriptional Activation; Transferase; Transgenic Mice; Unsaturated Fatty Acids; Up-Regulation; Ventricular; Workload; complex IV; cytotoxic; enzyme activity; fatty acid oxidation; feeding; improved; inhibitor/antagonist; mitochondrial dysfunction; mortality; prevent; programs; protective effect; protein expression; saturated fat; uptake

DESCRIPTION (provided by applicant): Recent studies suggest that excess lipid accumulation may play an important role in the pathophysiology of heart failure (HF), obesity, insulin resistance and diabetes. The cellular mechanisms that determine whether excess lipid accumulation is well tolerated or cytotoxic remains unknown. Although long chain saturated fatty acids (FA) are implicated in the synthesis of lipotoxic intermediates and ROS leading to enhanced cardiomyocyte dysfunction and apoptosis, recent evidence suggests that saturated FA enhance mitochondrial oxidative phosphorylation (OX PHOS) and electron transport chain (ETC) complex activities in HF. Furthermore, high fat feeding in rats with hypertension induced cardiomyopathy reduced left ventricular (LV) hypertrophy, improved LV contractile function, and prevented LV dilation. The mechanisms involved in a cardio-protective effect of a high saturated fat diet may include activation of peroxisome proliferator activated receptors (PPAR) and their co-activator PPAR gamma co-activator-1 (PGC-1) that operate to stimulate cardiac gene expression of the FA metabolic pathways and regulate OX PHOS and mitochondrial biogenesis respectively. The goal of this project is to investigate the impact of elevated dietary lipids on myocardial contractile and mitochondrial dysfunction in HF and hypertension induced cardiomyopathy. Studies will be performed in normal rats and two rat models of HF: coronary artery ligation induced HF and hypertension induced cardiomyopathy/failure. Specific Aim 1 will examine the effects of high fat diets (saturated and unsaturated) on myocardial contractile function (both at rest and under conditions of high workload), and mitochondrial OX PHOS and ETC complex activities in normal rats and in two HF models. Given the possible involvement of the PPAR/PGC-1 complex concomitant with high fat feeding, Specific Aim 2 will examine the effects of high fat diets in combination with either a FA oxidation inhibitor or a PPAR agonist on contractile and mitochondrial function in HF. Specific Aim 3 will examine the effects of saturated and unsaturated FA on gene transcription and post-translational modifications of proteins involved in the FA metabolic pathways and ETC complexes in both HF models. Specifically, mRNA and protein expression and activities of enzymes regulating FA metabolic pathways (eg PPAR alpha, PGC-1 alpha, carnitine palmitoyl transferase-l) and activities and modifications of the individual ETC complexes will be examined.

描述（由申请人提供）：最近的研究表明，多余的脂质积累可能在心力衰竭（HF），肥胖，胰岛素抵抗和糖尿病的病理生理学中起重要作用。确定过量脂质积累的细胞机制是否耐受性良好或细胞毒性仍然未知。尽管长链饱和脂肪酸（FA）与脂蛋白毒性中间体的合成和ROS的合成有关，从而导致心肌细胞功能障碍和凋亡增强，但最近的证据表明，饱和的FA增强了线粒体氧化磷酸化（OXPHOS）和电气传输链（等）复合物（等）的复合物。此外，高血压诱导心肌病的大鼠高脂肪进食可减少左心室（LV）肥大，提高LV收缩功能并预防LV扩张。高饱和脂肪饮食的心脏保护作用涉及的机制可能包括激活过氧化物酶体增殖物激活受体（PPAR）及其共激活剂PPAR伽马共活化剂1（PGC-1），可刺激FA代谢途径的心脏基因表达，并调节OxeSeasion acogocochrial alisocochorial seasision。该项目的目的是研究HF和高血压诱导的心肌病的饮食中脂质升高对心肌收缩和线粒体功能障碍的影响。研究将在正常大鼠和两种大鼠HF模型中进行：冠状动脉连接诱导的HF和高血压诱导的心肌病/衰竭。具体的目标1将检查高脂饮食（饱和和不饱和）对心肌收缩功能（在工作量高的情况下和条件下）以及正常大鼠和两种HF模型中的线粒体ox Phos和ETC复杂活动的影响。鉴于PPAR/PGC-1复合物可能与高脂喂养相关，因此特定的AIM 2将检查高脂饮食与FA氧化抑制剂或PPAR激动剂对收缩和线粒体功能在HF中的影响。具体目标3将检查饱和和不饱和FA对两个HF模型中FA代谢途径和ETC复合物中蛋白质基因转录和翻译后修饰的影响。具体而言，将检查调节FA代谢途径的酶的mRNA和蛋白质表达和活性（例如PPAR Alpha，PGC-1 Alpha，Carnitine Palmitoyl转移酶-L）以及各个单个等复合物的活性和修饰。