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Hypertrophic cardiomyopathy in high-fat diet-induced obesity: role of suppression of forkhead transcription factor and atrophy gene transcription.
Am J Physiol Heart Circ Physiol. 2008 Sep; 295(3):H1206-H1215.AJ

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, 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.

Authors+Show Affiliations

Center for Cardiovascular Research and Alternative Medicine, University of Wyoming College of Health Sciences, Laramie, WY 82071, USA.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

18641278

Citation

Fang, Cindy X., et al. "Hypertrophic Cardiomyopathy in High-fat Diet-induced Obesity: Role of Suppression of Forkhead Transcription Factor and Atrophy Gene Transcription." American Journal of Physiology. Heart and Circulatory Physiology, vol. 295, no. 3, 2008, pp. H1206-H1215.
Fang CX, Dong F, Thomas DP, et al. Hypertrophic cardiomyopathy in high-fat diet-induced obesity: role of suppression of forkhead transcription factor and atrophy gene transcription. Am J Physiol Heart Circ Physiol. 2008;295(3):H1206-H1215.
Fang, C. X., Dong, F., Thomas, D. P., Ma, H., He, L., & Ren, J. (2008). Hypertrophic cardiomyopathy in high-fat diet-induced obesity: role of suppression of forkhead transcription factor and atrophy gene transcription. American Journal of Physiology. Heart and Circulatory Physiology, 295(3), H1206-H1215. https://doi.org/10.1152/ajpheart.00319.2008
Fang CX, et al. Hypertrophic Cardiomyopathy in High-fat Diet-induced Obesity: Role of Suppression of Forkhead Transcription Factor and Atrophy Gene Transcription. Am J Physiol Heart Circ Physiol. 2008;295(3):H1206-H1215. PubMed PMID: 18641278.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Hypertrophic cardiomyopathy in high-fat diet-induced obesity: role of suppression of forkhead transcription factor and atrophy gene transcription. AU - Fang,Cindy X, AU - Dong,Feng, AU - Thomas,D Paul, AU - Ma,Heng, AU - He,Leilei, AU - Ren,Jun, Y1 - 2008/07/18/ PY - 2008/7/22/pubmed PY - 2008/10/17/medline PY - 2008/7/22/entrez SP - H1206 EP - H1215 JF - American journal of physiology. Heart and circulatory physiology JO - Am. J. Physiol. Heart Circ. Physiol. VL - 295 IS - 3 N2 - 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. SN - 0363-6135 UR - https://www.unboundmedicine.com/medline/citation/18641278/Hypertrophic_cardiomyopathy_in_high_fat_diet_induced_obesity:_role_of_suppression_of_forkhead_transcription_factor_and_atrophy_gene_transcription_ L2 - http://journals.physiology.org/doi/full/10.1152/ajpheart.00319.2008?url_ver=Z39.88-2003&rfr_id=ori:rid:crossref.org&rfr_dat=cr_pub=pubmed DB - PRIME DP - Unbound Medicine ER -