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Hypertrophic Cardiomyopathy in High Fat Diet-Induced Obesity: Role of Suppression of Forkhead Transcription Factor and Atrophy Gene Transcription | Author(s) | Cindy X Fang, Feng Dong, D. Paul Thomas, Heng Ma, Leilei He, Jun Ren | | Journal | Am J Physiol Heart Circ Physiol (July 18, 2008). doi:10.1152/ajpheart.00319.2008 | Abstract | 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, forkhead transcription factor Foxo3a, and atrophy genes MuRF1 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 months along with a food-restricted high fat weight control group. Echocardiography revealed decreased fractional shortening, increased end systolic diameter and cardiac hypertrophy in high fat obese but not the weight control mice. Cardiomyocytes from high fat obese but not weight control mice displayed contractile and intracellular Ca2+ defects including depressed maximal velocity of shortening/ relengthening, prolonged duration of shortening/relengthening, reduced intracellular Ca2+ rise and clearance. Caspase activities were greater in high fat obese but not weight control mouse hearts. Western blot analysis revealed enhanced basal Akt and Foxo3a phosphorylation, 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 atrogens atrogin-1 and MuRF1, upregulated hypertrophic markers GATA4 and CTNFR as well as unchanged calcineurin and proteasome ubiquitin in high fat obese mouse hearts. Transfection of H9C2 myoblast cells with dominant negative (DN) Foxo3a adenovirus mimicked palmitic acid (0.8 mM for 24 hrs)-induced GATA4 upregulation without additive effect. DN Foxo3a-induced upregulation of pAkt and repression of PTEN was abrogated by palmitic acid. These results suggest cardiac hypertrophic response in high fat diet-associated obesity at least in part through inactivation of Foxo3a by Akt pathway. |
| Keywords | myocytes, calcium, contractility, hyperswitch | Our Ref: 1672
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