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. ? ? ?

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL081857-02
Application #
7231482
Study Section
Myocardial Ischemia and Metabolism Study Section (MIM)
Program Officer
Ershow, Abby
Project Start
2006-05-15
Project End
2011-04-30
Budget Start
2007-05-01
Budget End
2008-04-30
Support Year
2
Fiscal Year
2007
Total Cost
$375,049
Indirect Cost
Name
Case Western Reserve University
Department
Physiology
Type
Schools of Medicine
DUNS #
077758407
City
Cleveland
State
OH
Country
United States
Zip Code
44106
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Cheng, Y; Li, W; McElfresh, T A et al. (2011) Changes in myofilament proteins, but not Ca²? regulation, are associated with a high-fat diet-induced improvement in contractile function in heart failure. Am J Physiol Heart Circ Physiol 301:H1438-46
Berthiaume, Jessica M; Bray, Molly S; McElfresh, Tracy A et al. (2010) The myocardial contractile response to physiological stress improves with high saturated fat feeding in heart failure. Am J Physiol Heart Circ Physiol 299:H410-21
Zhang, Zhaoyun; Liew, Chong Wee; Handy, Diane E et al. (2010) High glucose inhibits glucose-6-phosphate dehydrogenase, leading to increased oxidative stress and beta-cell apoptosis. FASEB J 24:1497-505
Christopher, Bridgette A; Huang, Hsuan-Ming; Berthiaume, Jessica M et al. (2010) Myocardial insulin resistance induced by high fat feeding in heart failure is associated with preserved contractile function. Am J Physiol Heart Circ Physiol 299:H1917-27
Leopold, Jane A; Loscalzo, Joseph (2009) Oxidative risk for atherothrombotic cardiovascular disease. Free Radic Biol Med 47:1673-706
Rennison, Julie H; McElfresh, Tracy A; Chen, Xiaoqin et al. (2009) Prolonged exposure to high dietary lipids is not associated with lipotoxicity in heart failure. J Mol Cell Cardiol 46:883-90
Ottaviano, Filomena G; Handy, Diane E; Loscalzo, Joseph (2008) Redox regulation in the extracellular environment. Circ J 72:1-16
Rennison, Julie H; McElfresh, Tracy A; Okere, Isidore C et al. (2008) Enhanced acyl-CoA dehydrogenase activity is associated with improved mitochondrial and contractile function in heart failure. Cardiovasc Res 79:331-40
Rennison, Julie H; McElfresh, Tracy A; Okere, Isidore C et al. (2007) High-fat diet postinfarction enhances mitochondrial function and does not exacerbate left ventricular dysfunction. Am J Physiol Heart Circ Physiol 292:H1498-506

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