Oral pretreatment with ebselen enhances heat shock protein 72 expression and reduces myocardial infarct size.
Reactive oxygen species (ROS) enhance myocardial ischemia-reperfusion (I/R) injury. Ebselen, a seleno-organic glutathione peroxidase (GPx) mimetic, has a protective effect against tissue injury induced by ROS. However, the cardio-protective effect of orally administered ebselen has never been investigated in cardiac I/R injury. We investigated the effects and mechanisms of orally administered ebselen on experimental myocardial infarction. Isolated perfused rabbit hearts underwent 30 min of global ischemia and 60 min of reperfusion, with or without oral administration of ebselen 24 h before I/R, with or without enhanced oxidative stress by H202 infusion for the first 1 min of reperfusion. The recovery of left ventricular developed pressure (LVDP) was significantly improved, and the myocardial infarct size was significantly reduced by ebselen. The recovery of LVDP and the myocardial infarct size were markedly aggravated by H202 infusion. These enhancements by H202 were dose-dependently suppressed by ebselen, along with a reduction in myocardial 8-hydroxydeoxyguanosine levels, a marker for oxidative DNA damage. The myocardial reduced glutathione (GSH) level was preserved by ebselen. Ebselen markedly enhanced myocardial heat shock protein (HSP) 72 expression. The cardioprotective effect of ebselen-induced HSP72 was confirmed by MTT assay in isolated cardiomyocytes using KNK437, a novel HSP inhibitor. In conclusion, an oral administration of ebselen 24 h before I/R provided excellent cardioprotective effects, at least in part through HSP72 induction and GSH preservation.
Baljinnyam
Erdenechimeg
E
Cardiovascular Division, Department of Internal Medicine, Asahikawa Medical College, Asahikawa, Japan.
Hasebe
Naoyuki
N
Morihira
Masahiko
M
Sumitomo
Kazuhiro
K
Matsusaka
Tomoyuki
T
Fujino
Takayuki
T
Fukuzawa
Jun
J
Ushikubi
Fumitaka
F
Kikuchi
Kenjiro
K
D000080242:8-Hydroxy-2'-Deoxyguanosine; D000284:Administration, Oral; D000818:Animals; D000975:Antioxidants / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D001393:Azoles / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D001559:Benzhydryl Compounds / Q000494:pharmacology; D002478:Cells, Cultured; D003849:Deoxyguanosine / Q000031:analogs & derivatives / Q000378:metabolism; D015870:Gene Expression / Q000187:drug effects; D005978:Glutathione / Q000187:drug effects; D050884:HSP72 Heat-Shock Proteins / Q000037:antagonists & inhibitors / Q000187:drug effects*; D006861:Hydrogen Peroxide / Q000494:pharmacology; D066298:In Vitro Techniques; D054833:Isoindoles; D008297:Male; D009203:Myocardial Infarction / Q000473:pathology / Q000517:prevention & control*; D015428:Myocardial Reperfusion Injury / Q000517:prevention & control*; D009206:Myocardium / Q000378:metabolism; D016566:Organoselenium Compounds / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D018384:Oxidative Stress / Q000187:drug effects; D011760:Pyrrolidinones / Q000494:pharmacology; D011817:Rabbits; D051381:Rats; D017207:Rats, Sprague-Dawley; D012643:Selenium / Q000378:metabolism; D013778:Tetrazolium Salts; D013844:Thiazoles
D000975:Antioxidants; D001393:Azoles; D001559:Benzhydryl Compounds; D050884:HSP72 Heat-Shock Proteins; D054833:Isoindoles; C410027:KNK 437; D016566:Organoselenium Compounds; D011760:Pyrrolidinones; D013778:Tetrazolium Salts; D013844:Thiazoles; C042986:ebselen; D000080242:8-Hydroxy-2'-Deoxyguanosine; D006861:Hydrogen Peroxide; C022616:thiazolyl blue; D003849:Deoxyguanosine; D005978:Glutathione; D012643:Selenium