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. ? ? ?
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