Pharmacological inhibition of GSK-3β produces late phase of cardioprotection in hyperlipidemic rat: possible involvement of HSP 72.
The acute, as well as late, phase of cardioprotection induced by ischemic preconditioning is abolished in hyperlipidemic (HL) rat heart. The pharmacological inhibition of glycogen synthase kinase-3β (GSK-3β), has earlier been reported to restore this attenuated acute cardioprotective effect. However, it not known whether GSK-3β inhibitors administered 24 h before the ischemic injury would restore the late cardioprotective in HL rat and, if yes, the role of heat shock protein 72 (HSP 72) in its modulation. Hyperlipidemia was produced in rat by feeding high-fat diet for 6 weeks. Isolated perfused rat heart was subjected to 30 min of ischemia followed by 120 min of reperfusion (I/R). Myocardial infarct size was estimated by triphenyltetrazolium chloride staining, while lactate dehydrogenase (LDH) and creatine kinase-MB (CK-MB) levels were analyzed from coronary effluent. GSK-3β inhibitors, SB 216763 (SB, 0.6 mg/kg, i.p.), and indirubin-3 monoxime (IND, 0.4 mg/kg, i.p.), administered 24 h before the isolation of heart, significantly decreased the I/R-induced myocardial infarct size and the release of LDH and CK-MB. The cardioprotective effect of GSK-3β inhibitors was significantly attenuated by quercetin (4 mg/kg, i.p.), a HSP 72 inhibitor, administered 1 h before the administration of SB or IND. That the late phase of cardioprotection induced by pretreatment with GSK-3β inhibitors is not attenuated/lost in HL rat heart is a new finding in our study. Our results indicate that HSP 72 acts on pathway of GSK-3β and plays a significant role in cardioprotection.
Department of Pharmacology, ISF College of Pharmacy, Moga, Punjab, India. hnyadav@gmail.com
Harlokesh Narayan
HN
Yadav
Manjeet
M
Singh
Pyare Lal
PL
Sharma
D000818:Animals; D059305:Diet, High-Fat; D038362:Glycogen Synthase Kinase 3 / Q000037:antagonists & inhibitors / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta; D050884:HSP72 Heat-Shock Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D006949:Hyperlipidemias / Q000378:metabolism*; D007211:Indoles / Q000008:administration & dosage; D019157:Ischemic Preconditioning, Myocardial; D008297:Male; D008301:Maleimides / Q000008:administration & dosage; D009203:Myocardial Infarction / Q000473:pathology; D009206:Myocardium / Q000378:metabolism*; D009924:Organ Culture Techniques; D010091:Oximes / Q000008:administration & dosage; D011794:Quercetin / Q000008:administration & dosage; D051381:Rats; D017208:Rats, Wistar; D015427:Reperfusion Injury / Q000378:metabolism / Q000473:pathology
D050884:HSP72 Heat-Shock Proteins; D007211:Indoles; D008301:Maleimides; D010091:Oximes; C417521:SB 216763; C474021:indirubin-3'-monoxime; D011794:Quercetin; D000071679:Glycogen Synthase Kinase 3 beta; C000605508:Gsk3b protein, rat; D038362:Glycogen Synthase Kinase 3