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This Article Full Text Full Text (PDF) All Versions of this Article: 294/2/H936    most recent 00870.2007v1 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 Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Web of Science (8) Citing Articles via Google Scholar Google Scholar Articles by Zhao, G. Articles by Kliewer, S. A. Search for Related Content PubMed PubMed Citation Articles by Zhao, G. Articles by Kliewer, S. A.

Overexpression of pyruvate dehydrogenase kinase 4 in heart perturbs metabolism and exacerbates calcineurin-induced cardiomyopathy

Departments of ¹Molecular Biology, ²Internal Medicine, ³Pathology, and ⁴Pharmacology and ⁵Advanced Imaging Research Center, University of Texas Southwestern Medical Center, Dallas, Texas; and ⁶Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, Indiana

Submitted 25 July 2007 ; accepted in final form 3 December 2007

The heart adapts to changes in nutritional status and energy demands by adjusting its relative metabolism of carbohydrates and fatty acids. Loss of this metabolic flexibility such as occurs in diabetes mellitus is associated with cardiovascular disease and heart failure. To study the long-term consequences of impaired metabolic flexibility, we have generated mice that overexpress pyruvate dehydrogenase kinase (PDK)4 selectively in the heart. Hearts from PDK4 transgenic mice have a marked decrease in glucose oxidation and a corresponding increase in fatty acid catabolism. Although no overt cardiomyopathy was observed in the PDK4 transgenic mice, introduction of the PDK4 transgene into mice expressing a constitutively active form of the phosphatase calcineurin, which causes cardiac hypertrophy, caused cardiomyocyte fibrosis and a striking increase in mortality. These results demonstrate that cardiac-specific overexpression of PDK4 is sufficient to cause a loss of metabolic flexibility that exacerbates cardiomyopathy caused by the calcineurin stress-activated pathway.

fatty acid; hypertrophy; transgenic mice

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