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

Division of Cardiovascular Diseases, Department of Medicine, and Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Mayo Foundation, Rochester, Minnesota 55905 Modulation of mitochondrial respiratory chain, dehydrogenase, and nucleotide-metabolizing enzyme activities is...

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Veröffentlicht in:American journal of physiology. Heart and circulatory physiology 2003-04, Vol.284 (4), p.H1048-H1056
Hauptverfasser: Dzeja, Petras P, Bast, Peter, Ozcan, Cevher, Valverde, Arturo, Holmuhamedov, Ekshon L, Van Wylen, David G. L, Terzic, Andre
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container_issue 4
container_start_page H1048
container_title American journal of physiology. Heart and circulatory physiology
container_volume 284
creator Dzeja, Petras P
Bast, Peter
Ozcan, Cevher
Valverde, Arturo
Holmuhamedov, Ekshon L
Van Wylen, David G. L
Terzic, Andre
description Division of Cardiovascular Diseases, Department of Medicine, and Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Mayo Foundation, Rochester, Minnesota 55905 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 IC 50 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. potassium channel openers; mitochondria; ATP-sensitive potassium channel; dehydrogenase
doi_str_mv 10.1152/ajpheart.00847.2002
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ispartof American journal of physiology. Heart and circulatory physiology, 2003-04, Vol.284 (4), p.H1048-H1056
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source MEDLINE; American Physiological Society Paid; EZB-FREE-00999 freely available EZB journals
subjects Adenosine Triphosphatases - metabolism
Adenosine Triphosphate - metabolism
Amides - metabolism
Animals
Cardiovascular Agents - pharmacology
Decanoic Acids - pharmacology
Diazoxide - pharmacology
Electron Transport - drug effects
Flavin-Adenine Dinucleotide - pharmacology
Hydroxy Acids - pharmacology
Ischemic Preconditioning
Kinetics
Malondialdehyde - metabolism
Mitochondria, Heart - drug effects
Mitochondria, Heart - enzymology
Nucleotides - pharmacology
Oxidative Stress - drug effects
Rats
Reactive Oxygen Species - metabolism
Succinate Dehydrogenase - metabolism
Succinates
Superoxides - metabolism
title Targeting nucleotide-requiring enzymes: implications for diazoxide-induced cardioprotection
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