Targeting nucleotide-requiring enzymes: Implications for diazoxide-induced cardioprotection

Petras P. Dzeja, Peter Bast, Cevher Ozcan, Arturo Valverde, Ekshon L. Holmuhamedov, David G.L. Van Wylen, Andre Terzic

Research output: Contribution to journalArticle

89 Scopus citations

Abstract

Modulation of mitochondrial respiratory chain, dehydrogenase, and nucleotide-metabolizing enzyme activities is fundamental to cellular protection. Here, we demonstrate that the potassium channel opener diazoxide, within its cardioprotective concentration range, modulated the activity of flavin adenine dinucleotide-dependent succinate dehydrogenase with an IC50 of 32 μM and reduced the rate of succinate-supported generation of reactive oxygen species (ROS) in heart mitochondria. 5-Hydroxydecanoic fatty acid circumvented diazoxide-inhibited succinate dehydrogenase-driven electron flow, indicating a metabolism-dependent supply of redox equivalents to the respiratory chain. In perfused rat hearts, diazoxide diminished the generation of malondialdehyde, a marker of oxidative stress, which, however, increased on diazoxide washout. This effect of diazoxide mimicked ischemic preconditioning and was associated with reduced oxidative damage on ischemia-reperfusion. Diazoxide reduced cellular and mitochondrial ATPase activities, along with nucleotide degradation, contributing to preservation of myocardial ATP levels during ischemia. Thus, by targeting nucleotide-requiring enzymes, particularly mitochondrial succinate dehydrogenase and cellular ATPases, diazoxide reduces ROS generation and nucleotide degradation, resulting in preservation of myocardial energetics under stress.

Original languageEnglish (US)
Pages (from-to)H1048-H1056
JournalAmerican Journal of Physiology - Heart and Circulatory Physiology
Volume284
Issue number4 53-4
DOIs
StatePublished - Apr 1 2003

Keywords

  • ATP-sensitive potassium channel
  • Dehydrogenase
  • Mitochondria
  • Potassium channel openers

ASJC Scopus subject areas

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

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