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

基本信息

批准号：
7837058
负责人：
MARGARET P CHANDLER
金额：
$ 26.68万
依托单位：
CASE WESTERN RESERVE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-07-15 至 2012-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7837058
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 Coronary artery Development Diabetes Mellitus Diet Dietary Fats Eating Electron Transport 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 Physiology Play Polyunsaturated Fatty Acids Post-Translational Protein Processing Rattus Research Personnel Respiration Rest Role Saturated Fatty Acids Stress Time 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

项目摘要

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，过量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发挥重要作用。决定过量脂质积累是否具有良好耐受性或细胞毒性的细胞机制仍然未知。虽然长链饱和脂肪酸 (FA) 参与脂毒性中间体和 ROS 的合成，导致心肌细胞功能障碍和细胞凋亡增强，但最近的证据表明，饱和 FA 增强线粒体氧化磷酸化 (OX PHOS) 和电子传递链 (ETC) 复合物的活性在高频中。此外，高血压诱发的心肌病大鼠的高脂肪喂养可减少左心室（LV）肥厚，改善左心室收缩功能，并防止左心室扩张。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 γ 共激活剂-1 (PGC-1)，这些受体可刺激心脏基因表达FA 代谢途径并分别调节 OX PHOS 和线粒体生物发生。该项目的目标是研究膳食脂质升高对心力衰竭和高血压引起的心肌病中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心力衰竭大鼠模型中进行：冠状动脉结扎诱发的心力衰竭和高血压诱发的心肌病/衰竭。具体目标 1 将检查高脂肪饮食（饱和和不饱和）对正常大鼠和两个 HF 模型中心肌收缩功能（在休息和高负荷条件下）以及线粒体 OX PHOS 和 ETC 复合物活动的影响。鉴于高脂肪喂养可能涉及 PPAR/PGC-1 复合物，具体目标 2 将检查高脂肪饮食与 FA 氧化抑制剂或 PPAR 激动剂联合使用对心衰患者收缩和线粒体功能的影响。具体目标 3 将检查饱和和不饱和 FA 对两种 HF 模型中 FA 代谢途径和 ETC 复合物涉及的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（例如PPARα、PGC-1α、肉碱棕榈酰转移酶-1）的mRNA和蛋白质表达和活性以及各个ETC复合物的活性和修饰。