title: Hypercholesterolemia abrogates the cardioprotection of ischemic postconditioning in isolated rat heart: roles of glycogen synthase kinase-3β and the mitochondrial permeability transition pore.
abstract: Ischemic postconditioning (IPO) reduces lethal reperfusion injury under normal conditions, but its effectiveness in hypercholesterolemia (HC) is disputed. We measured the cardioprotection of IPO in hypercholesterolemic rats and determined the roles of glycogen synthase kinase-3β (GSK-3β) and the mitochondrial permeability transition pore (mPTP). Isolated rat hearts underwent 30-min global ischemia and 120-min reperfusion. Postconditioning protocol induced six cycles of 10s ischemia and 10s reperfusion at the onset of the reperfusion. Myocardial infarct size was estimated by triphenyltetrazolium chloride staining and cardiomyocyte apoptosis was assessed by TUNEL staining. GSK-3β phosphorylation was measured by immunoblotting. The opening of mPTP was measured by NAD(+) content in myocardium. In normocholesterolemia (NC) groups, infarct size and cardiomyocyte apoptosis were significantly reduced after IPO. These reductions were completely abolished by HC, as evidenced by a similar infarct size and cardiomyocyte apoptosis observed between the IPO-HC and IR (ischemia-reperfusion)-HC groups. GSK-3β phosphorylation was significantly higher in the IPO-NC than the IPO-HC group. In addition, NAD(+) content in myocardium, a marker of mPTP opening, was higher in the IPO-NC group than the IPO-HC group. In conclusion, cardioprotection of IPO is blocked by hypercholesterolemia. This might be due to the impairment of phosphorylation of GSK-3β and attenuation of mPTP opening.
authors.affiliation: Department of Cardiology, The First Affiliated Hospital of China Medical University, 155th North of Nanjing Street, Heping District, Shenyang, 110001, Liaoning, China.
authors.forename: Nan
authors.initials: N
authors.lastname: Wu
authors.forename: Xiaowen
authors.initials: X
authors.lastname: Zhang
authors.forename: Yuee
authors.initials: Y
authors.lastname: Guan
authors.forename: Wenqi
authors.initials: W
authors.lastname: Shu
authors.forename: Pengyu
authors.initials: P
authors.lastname: Jia
authors.forename: Dalin
authors.initials: D
authors.lastname: Jia
mesh_terms: D000818:Animals; D017209:Apoptosis; D019610:Cytoprotection; D005786:Gene Expression Regulation; D038362:Glycogen Synthase Kinase 3 / Q000235:genetics* / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta; D006937:Hypercholesterolemia / Q000235:genetics* / Q000378:metabolism / Q000503:physiopathology; D057775:Ischemic Postconditioning; D008297:Male; D033681:Mitochondrial Membrane Transport Proteins / Q000235:genetics* / Q000378:metabolism; D000083162:Mitochondrial Permeability Transition Pore; D032383:Myocytes, Cardiac / Q000378:metabolism / Q000473:pathology; D009924:Organ Culture Techniques; D010766:Phosphorylation; D051381:Rats; D017208:Rats, Wistar; D015427:Reperfusion Injury / Q000235:genetics* / Q000378:metabolism / Q000503:physiopathology
chemical_list: D033681:Mitochondrial Membrane Transport Proteins; D000083162:Mitochondrial Permeability Transition Pore; D000071679:Glycogen Synthase Kinase 3 beta; C000605508:Gsk3b protein, rat; D038362:Glycogen Synthase Kinase 3