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

描述(申请人提供)：最近的研究表明，过多的脂肪堆积可能在心力衰竭(HF)、肥胖、胰岛素抵抗和糖尿病的病理生理过程中发挥重要作用。决定过多的脂肪堆积是耐受性好还是细胞毒性的细胞机制仍不清楚。虽然长链饱和脂肪酸(FA)参与合成脂毒中间体和ROS，导致心肌细胞功能障碍和细胞凋亡，但最近的证据表明，饱和FA增强了HF中线粒体氧化磷酸化(OX PHOS)和电子传输链(ETC)复合体的活性。此外，高脂喂养可减轻高血压心肌病大鼠的左心室肥厚，改善左心室收缩功能，防止左心室扩张。高饱和脂肪饮食心脏保护作用的机制可能包括激活过氧化体增殖物激活受体(PPAR)及其共激活物PPAR-γ共激活物-1(PGC-1)，分别刺激FA代谢途径的心脏基因表达和调节OX-PHOS和线粒体的生物发生。本项目的目的是研究高脂饮食对心力衰竭和高血压所致心肌病心肌收缩和线粒体功能障碍的影响。将在正常大鼠和两种心力衰竭大鼠模型上进行研究：冠状动脉结扎诱导心力衰竭和高血压诱导的心肌病/衰竭。具体目的1研究高脂饮食(饱和和不饱和)对正常大鼠和两种心力衰竭模型大鼠心肌收缩功能(静息状态和高负荷状态下)、线粒体OX-PHOS等复合体活性的影响。鉴于PPAR/PGC-1复合体可能参与高脂肪喂养，特定目标2将研究高脂肪饮食与FA氧化抑制剂或PPAR激动剂联合使用对HF收缩和线粒体功能的影响。具体目标3将研究饱和和不饱和FA对两种心力衰竭模型中FA代谢途径和ETC复合体中涉及的蛋白质的基因转录和翻译后修饰的影响。具体地说，将检测调控FA代谢途径的酶(如PPARα、PGC-1α、肉碱棕榈酰转移酶-L)的基因和蛋白表达和活性，以及单个ETC复合体的活性和修饰。

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.