ANG II causes insulin resistance and induces cardiac metabolic switch and inefficiency: A critical role of PDK4

Jun Mori, Osama Abo Alrob, Cory S. Wagg, Robert A. Harris, Gary D. Lopaschuk, Gavin Y. Oudit

Research output: Contribution to journalArticle

79 Scopus citations

Abstract

The renin-angiotensin system (RAS) may alter cardiac energy metabolism in heart failure. Angiotensin II (ANG II), the main effector of the RAS in heart failure, has emerged as an important regulator of cardiac hypertrophy and energy metabolism. We studied the metabolic perturbations and insulin response in an ANG II-induced hypertrophy model. Ex vivo heart perfusion showed that hearts from ANG II-treated mice had a lower response to insulin with significantly reduced rates of glucose oxidation in association with increased pyruvate dehydrogenase kinase 4 (PDK4) levels. Palmitate oxidation rates were significantly reduced in response to insulin in vehicle-treated hearts but remained unaltered in ANG II-treated hearts. Furthermore, phosphorylation of Akt was also less response to insulin in ANG II-treated wild-type (WT) mice, suggestive of insulin resistance. We evaluated the role of PDK4 in the ANG II-induced pathology and showed that deletion of PDK4 prevented ANG II-induced diastolic dysfunction and normalized glucose oxidation to basal levels. ANG II-induced reduction in the levels of the deacetylase, SIRT3, was associated with increased acetylation of pyruvate dehydrogenase (PDH) and a reduced PDH activity. In conclusion, our findings show that a combination of insulin resistance and decrease in PDH activity are involved in ANG II-induced reduction in glucose oxidation, resulting in cardiac inefficiency. ANG II reduces PDH activity via acetylation of PDH complex, as well as increased phosphorylation in response to increased PDK4 levels.

Original languageEnglish (US)
Pages (from-to)H1103-H1113
JournalAmerican Journal of Physiology - Heart and Circulatory Physiology
Volume304
Issue number8
DOIs
StatePublished - Jun 10 2013

Keywords

  • ANG II
  • Cardiac metabolism
  • Diastolic dysfunction
  • Insulin resistance
  • Sirtuin

ASJC Scopus subject areas

  • Physiology
  • Physiology (medical)
  • Cardiology and Cardiovascular Medicine
  • Medicine(all)

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