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This Article Full Text Full Text (PDF) All Versions of this Article: 294/3/H1388    most recent 01339.2007v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in ISI Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Pillai, J. B. Articles by Gupta, M. P. Search for Related Content PubMed PubMed Citation Articles by Pillai, J. B. Articles by Gupta, M. P.

Activation of SIRT1, a class III histone deacetylase, contributes to fructose feeding-mediated induction of the -myosin heavy chain expression

¹Division of Cardiothoracic Surgery, Department of Surgery, Committee on Molecular Medicine and Pathology, The University of Chicago, Chicago; and ²The Heart Institute of Children, Hope Children's Hospital, Oak Lawn, Illinois

Submitted 4 November 2007 ; accepted in final form 8 January 2008

Fructose feeding has been shown to induce the cardiac -myosin heavy chain (MHC) expression and protect the heart from ischemia- and reperfusion-mediated cell injury. This study was designed to investigate the mechanism involved in the effect of this sugar on MHC gene expression and cardiac protection. Adult mice were fed with a 6-propyl-2-thiouracil (PTU) diet or PTU combined with a fructose-rich diet. PTU treatment made animals hypothyroid and that resulted in total replacement of cardiac -MHC with the β-MHC isoform. Addition of fructose in the PTU diet led to reexpression of the -MHC isoform to a significant level. Similar induction of -MHC expression was also seen when PTU diet was combined with resveratrol, an agonist of sirtuin (SIRT) 1 deacetylase. Analysis of heart lysate of these animals indicated that fructose feeding augmented the NAD-to-NADH ratio and the cardiac SIRT1 levels, thus suggesting a role of SIRT1 in fructose-mediated activation of -MHC isoform. To analyze a direct effect of SIRT1 on MHC isoform expression, we generated transgenic mice expressing SIRT1 in the heart. Treatment of these transgenic mice with PTU diet did not lead to disappearance of -MHC, as it did in the nontransgenic animals. SIRT1 overexpression also activated the -MHC gene promoter in transient transfection assays, thus confirming a role of SIRT1 in the induction of -MHC expression. Fructose feeding also attenuated the MHC isoform shift and blocked the cardiac hypertrophy response associated with pressure overload, which was again associated with the induction of cardiac SIRT1 levels. These results demonstrate that fructose feeding protects the heart by induction of the SIRT1 deacetylase and highlight its role in the induction of -MHC gene expression.

sirtuins; resveratrol; cardiac hypertrophy