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

Guixiang Zhao, Ho Jeoung Nam, Shawn C. Burgess, Kimberly A. Rosaaen-Stowe, Takeshi Inagaki, Shuaib Latif, John M. Shelton, John McAnally, Rhonda Bassel-Duby, Robert A. Harris, James A. Richardson, Steven A. Kliewer

Research output: Contribution to journalArticle

67 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)H936-H943
JournalAmerican Journal of Physiology - Heart and Circulatory Physiology
Volume294
Issue number2
DOIs
StatePublished - Feb 1 2008

Keywords

  • Fatty acid
  • Hypertrophy
  • Transgenic mice

ASJC Scopus subject areas

  • Physiology

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    Zhao, G., Nam, H. J., Burgess, S. C., Rosaaen-Stowe, K. A., Inagaki, T., Latif, S., Shelton, J. M., McAnally, J., Bassel-Duby, R., Harris, R. A., Richardson, J. A., & Kliewer, S. A. (2008). Overexpression of pyruvate dehydrogenase kinase 4 in heart perturbs metabolism and exacerbates calcineurin-induced cardiomyopathy. American Journal of Physiology - Heart and Circulatory Physiology, 294(2), H936-H943. https://doi.org/10.1152/ajpheart.00870.2007