Cellular remodeling in heart failure disrupts KATP channel-dependent stress tolerance

Denice M. Hodgson, Leonid V. Zingman, Garvan C. Kane, Carmen Perez-Terzic, Martin Bienengraeber, Cevher Ozcan, Richard J. Gumina, Darko Pucar, Fergus O'Coclain, Douglas L. Mann, Alexey E. Alekseev, Andre Terzic

Research output: Contribution to journalArticle

79 Scopus citations

Abstract

ATP-sensitive potassium (KATP) channels are required for maintenance of homeostasis during the metabolically demanding adaptive response to stress. However, in disease, the effect of cellular remodeling on KATP channel behavior and associated tolerance to metabolic insult is unknown. Here, transgenic expression of tumor necrosis factor α induced heart failure with typical cardiac structural and energetic alterations. In this paradigm of disease remodeling, KATP channels responded aberrantly to metabolic signals despite intact intrinsic channel properties, implicating defects proximal to the channel. Indeed, cardiomyocytes from failing hearts exhibited mitochondrial and creatine kinase deficits, and thus a reduced potential for metabolic signal generation and transmission. Consequently, KATP channels failed to properly translate cellular distress under metabolic challenge into a protective membrane response. Failing hearts were excessively vulnerable to metabolic insult, demonstrating cardiomyocyte calcium loading and myofibrillar contraction banding, with tolerance improved by KATP channel openers. Thus, disease-induced KATP channel metabolic dysregulation is a contributor to the pathobiology of heart failure, illustrating a mechanism for acquired channelopathy.

Original languageEnglish (US)
Pages (from-to)1732-1742
Number of pages11
JournalEMBO Journal
Volume22
Issue number8
DOIs
StatePublished - Apr 15 2003

Keywords

  • ATP-sensitive potassium channel
  • Energy metabolism
  • Heart failure
  • Potassium channel openers
  • TNFα

ASJC Scopus subject areas

  • Neuroscience(all)
  • Molecular Biology
  • Biochemistry, Genetics and Molecular Biology(all)
  • Immunology and Microbiology(all)

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    Hodgson, D. M., Zingman, L. V., Kane, G. C., Perez-Terzic, C., Bienengraeber, M., Ozcan, C., Gumina, R. J., Pucar, D., O'Coclain, F., Mann, D. L., Alekseev, A. E., & Terzic, A. (2003). Cellular remodeling in heart failure disrupts KATP channel-dependent stress tolerance. EMBO Journal, 22(8), 1732-1742. https://doi.org/10.1093/emboj/cdg192