Hypertrophic cardiomyopathy in high-fat diet-induced obesity: role of suppression of forkhead transcription factor and atrophy gene transcription.
Cellular hypertrophy is regulated by coordinated pro- and antigrowth machineries. Foxo transcription factors initiate an atrophy-related gene program to counter hypertrophic growth. This study was designed to evaluate the role of Akt, the forkhead transcription factor Foxo3a, and atrophy genes muscle-specific RING finger (MuRF)-1 and atrogin-1 in cardiac hypertrophy and contractile dysfunction associated with high-fat diet-induced obesity. Mice were fed a low- or high-fat diet for 6 mo along with a food-restricted high-fat weight control group. Echocardiography revealed decreased fractional shortening and increased end-systolic diameter and cardiac hypertrophy in high-fat obese but not in weight control mice. Cardiomyocytes from high-fat obese but not from weight control mice displayed contractile and intracellular Ca2+ defects including depressed maximal velocity of shortening/relengthening, prolonged duration of shortening/relengthening, and reduced intracellular Ca2+ rise and clearance. Caspase activities were greater in high-fat obese but not in weight control mouse hearts. Western blot analysis revealed enhanced basal Akt and Foxo3a phosphorylation and reduced insulin-stimulated phosphorylation of Akt and Foxo3a without changes in total protein expression of Akt and Foxo3a in high-fat obese hearts. RT-PCR and immunoblotting results displayed reduced levels of the atrogens atrogin-1 and MuRF-1, the upregulated hypertrophic markers GATA4 and ciliary neurotrophic factor receptor-alpha, as well as the unchanged calcineurin and proteasome ubiquitin in high-fat obese mouse hearts. Transfection of H9C2 myoblast cells with dominant-negative Foxo3a adenovirus mimicked palmitic acid (0.8 mM for 24 h)-induced GATA4 upregulation without an additive effect. Dominant-negative Foxo3a-induced upregulation of pAkt and repression of phosphatase and tensin homologue were abrogated by palmitic acid. These results suggest a cardiac hypertrophic response in high-fat diet-associated obesity at least in part through inactivation of Foxo3a by the Akt pathway.
Fang
Cindy X
CX
Center for Cardiovascular Research and Alternative Medicine, University of Wyoming College of Health Sciences, Laramie, WY 82071, USA.
Dong
Feng
F
Thomas
D Paul
DP
Ma
Heng
H
He
Leilei
L
Ren
Jun
J
D000818:Animals; D017209:Apoptosis / Q000235:genetics; D001284:Atrophy / Q000235:genetics; D015415:Biomarkers / Q000378:metabolism; D015153:Blotting, Western; D019703:Calcineurin / Q000378:metabolism; D020013:Calcium Signaling / Q000502:physiology; D006332:Cardiomegaly / Q000209:etiology* / Q000473:pathology*; D053148:Caspase 3 / Q000378:metabolism; D053179:Caspase 7 / Q000378:metabolism; D004032:Diet; D004041:Dietary Fats / Q000633:toxicity*; D004562:Electrocardiography; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors / Q000235:genetics*; D008297:Male; D051379:Mice; D009200:Myocardial Contraction / Q000502:physiology; D032383:Myocytes, Cardiac / Q000502:physiology; D009765:Obesity / Q000150:complications* / Q000473:pathology*; D014158:Transcription, Genetic; D025801:Ubiquitin / Q000378:metabolism
D015415:Biomarkers; D004041:Dietary Fats; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors; C474033:FoxO3 protein, mouse; D025801:Ubiquitin; D019703:Calcineurin; D053148:Caspase 3; D053179:Caspase 7