Targeting nucleotide-requiring enzymes: implications for diazoxide-induced cardioprotection.
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 microM 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.
Dzeja
Petras P
PP
Department of Medicine, Mayo Clinic, Mayo Foundation, Rochester, MN 55905, USA.
Bast
Peter
P
Ozcan
Cevher
C
Valverde
Arturo
A
Holmuhamedov
Ekshon L
EL
Van Wylen
David G L
DG
Terzic
Andre
A
D000251:Adenosine Triphosphatases / Q000378:metabolism; D000255:Adenosine Triphosphate / Q000378:metabolism; D000577:Amides / Q000378:metabolism; D000818:Animals; D002317:Cardiovascular Agents / Q000494:pharmacology*; D003652:Decanoic Acids / Q000494:pharmacology; D003981:Diazoxide / Q000494:pharmacology*; D004579:Electron Transport / Q000187:drug effects; D005182:Flavin-Adenine Dinucleotide / Q000494:pharmacology; D006880:Hydroxy Acids / Q000494:pharmacology; D019194:Ischemic Preconditioning; D007700:Kinetics; D008315:Malondialdehyde / Q000378:metabolism; D008929:Mitochondria, Heart / Q000187:drug effects / Q000201:enzymology*; D009711:Nucleotides / Q000494:pharmacology*; D018384:Oxidative Stress / Q000187:drug effects; D051381:Rats; D017382:Reactive Oxygen Species / Q000378:metabolism; D013385:Succinate Dehydrogenase / Q000378:metabolism; D013386:Succinates; D013481:Superoxides / Q000378:metabolism
D000577:Amides; D002317:Cardiovascular Agents; D003652:Decanoic Acids; D006880:Hydroxy Acids; D009711:Nucleotides; D017382:Reactive Oxygen Species; D013386:Succinates; D013481:Superoxides; D005182:Flavin-Adenine Dinucleotide; D008315:Malondialdehyde; C052853:5-hydroxydecanoic acid; D000255:Adenosine Triphosphate; D013385:Succinate Dehydrogenase; D000251:Adenosine Triphosphatases; D003981:Diazoxide; C011116:succinamide