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

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中起重要作用。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尚不清楚。虽然长链饱和脂肪酸（FA）与脂毒性中间体和ROS的合成有关，导致心肌细胞功能障碍和凋亡的增强，但最近的证据表明，饱和脂肪酸可增强HF中线粒体氧化磷酸化（OX PHOS）和电子传递链（ETC）复合物的活性。此外，高脂肪喂养高血压性心肌病大鼠可降低左室肥厚，改善左室收缩功能，阻止左室扩张。高饱和脂肪饮食对心脏保护作用的机制可能包括激活过氧化物酶体增殖物激活受体（PPAR）及其共激活物PPAR γ共激活物-1 (PGC-1)，它们分别刺激心脏FA代谢途径的基因表达，调节OX PHOS和线粒体生物发生。本项目的目的是研究膳食脂质升高对心衰和高血压引起的心肌病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HF大鼠模型中进行：冠状动脉结扎引起的HF和高血压引起的心肌病/心力衰竭。具体目标1将在正常大鼠和两种HF模型中研究高脂肪饮食（饱和和不饱和）对心肌收缩功能（静止和高负荷条件下）以及线粒体OX PHOS和ETC复合物活性的影响。考虑到PPAR/PGC-1复合物可能与高脂肪喂养有关，Specific Aim 2将研究高脂肪饮食与FA氧化抑制剂或PPAR激动剂联合使用对心衰患者收缩和线粒体功能的影响。特异性目标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复合物相关蛋白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（如PPAR α， PGC-1 α，肉毒碱棕榈酰转移酶-1）的mRNA和蛋白质表达和活性以及单个ETC复合物的活性和修饰。

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.