Deactivation of peroxisome proliferator–activated receptor-α during cardiac hypertrophic growth
Philip M. Barger, … , Carla J. Weinheimer, Daniel P. Kelly
Philip M. Barger, … , Carla J. Weinheimer, Daniel P. Kelly
Published June 15, 2000
Citation Information: J Clin Invest. 2000;105(12):1723-1730. https://doi.org/10.1172/JCI9056.
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Article

Deactivation of peroxisome proliferator–activated receptor-α during cardiac hypertrophic growth

Abstract

We sought to delineate the molecular regulatory events involved in the energy substrate preference switch from fatty acids to glucose during cardiac hypertrophic growth. α1-adrenergic agonist–induced hypertrophy of cardiac myocytes in culture resulted in a significant decrease in palmitate oxidation rates and a reduction in the expression of the gene encoding muscle carnitine palmitoyltransferase I (M-CPT I), an enzyme involved in mitochondrial fatty acid uptake. Cardiac myocyte transfection studies demonstrated that M-CPT I promoter activity is repressed during cardiac myocyte hypertrophic growth, an effect that mapped to a peroxisome proliferator–activated receptor-α (PPARα) response element. Ventricular pressure overload studies in mice, together with PPARα overexpression studies in cardiac myocytes, demonstrated that, during hypertrophic growth, cardiac PPARα gene expression falls and its activity is altered at the posttranscriptional level via the extracellular signal–regulated kinase mitogen-activated protein kinase pathway. Hypertrophied myocytes exhibited reduced capacity for cellular lipid homeostasis, as evidenced by intracellular fat accumulation in response to oleate loading. These results indicate that during cardiac hypertrophic growth, PPARα is deactivated at several levels, leading to diminished capacity for myocardial lipid and energy homeostasis.

Authors

Philip M. Barger, Jon M. Brandt, Teresa C. Leone, Carla J. Weinheimer, Daniel P. Kelly

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Figure 3

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PPARα-mediated transcriptional control of MCPT.Luc.781 is blocked in the...
PPARα-mediated transcriptional control of MCPT.Luc.781 is blocked in the hypertrophied cardiac myocyte. (a) Shown is the homologous promoter–reporter plasmid, MCPT.Luc.781, containing the PPARα response element, FARE-1, located upstream of two untranslated exons, 1A and 1B (9, 26) (top). Either MCPT.Luc.781 or a construct containing FARE-1 mutated at the position underlined in the FARE-1 DNA sequence (MCPT.Luc.781.m1) was transfected into rat neonatal cardiac myocytes in serum-free media, followed by a 60-hour exposure to either vehicle (water) control or PE. Exposure to oleate (50 μM or 250 μM) or vehicle (0) began 12 hours after transfection and was continued for 48 hours. Bars represent mean (± SEM) luciferase activity (in relative luciferase units, or RLU) in cardiac myocytes exposed to the indicated concentrations of oleate, and incubated in the absence (C) or presence of PE. Values shown were corrected for transfection efficiency using the activity of cotransfected pSV40–β-Gal plasmid and normalized (= 1.0) to the values obtained with cells exposed to vehicle alone. ASignificantly different from control cardiac myocytes. (b) Activity of the heterologous promoter–luciferase gene reporter plasmid (FARE1)2TKLuc (left) or (ACO)3TKLuc (right) in the presence of pCDM.PPAR. The values shown are RLU corrected for the activity of cotransfected pSV40–β-Gal and are normalized (= 1.0) to the activity of the reporter construct in identically treated cells cotransfected with vector backbone [pCDM(-)] and exposed to vehicle. The data shown represent the mean (± SEM) of three independent experiments. ASignificantly different (P < 0.05) from the control value. BSignificantly different from value obtained in the presence of oleate or ETYA without PE added.