title: Inhibition of Rho-kinase by fasudil restores the cardioprotection of ischemic postconditioninng in hypercholesterolemic rat heart.
abstract: Ischemic postconditioning (IPoC) reduces lethal reperfusion injury under normal conditions, but its effectiveness is blocked by hypercholesterolemia. The present study aimed to determine whether the inhibition of Rho‑kinase by fasudil restores the cardioprotection of IPoC in the hypercholesterolemic rat heart, and to elucidate the potential mechanisms underlying this process. The isolated rat hearts underwent 30 min global ischemia and 120 min reperfusion. IPoC was induced by six cycles of 10 sec ischemia and 10 sec reperfusion at the onset of the reperfusion. Fasudil was administered 15 min prior to ischemia, and wortmannin and L‑NAME were administered following IPoC. The myocardial infarct size, apoptosis, myocardial nitric oxide (NO) content and Rho‑kinase activity, as well as the activation of the phosphatidylinositol 3‑kinase/Akt/endothelial nitric oxide synthase (PI3K/Akt/eNOS) pathway, were examined. The results revealed that IPoC and 1 µM fasudil treatment alone failed to reduce the infarct size and apoptosis rate. However, IPoC combined with 1 µM fasudil treatment or 10 µM fasudil treatment alone restored the cardioprotection as evidenced by the decreasing in infarct size and apoptosis rate, whereas it was blocked by the administration of wortmannin or L‑NAME. Furthermore, IPoC combined with 1 µM fasudil treatment also enhanced the phosphorylation of Akt and eNOS and conferred a significant increase in the content of NO. By contrast, no significant improvements were demonstrated in the phosphorylation of Akt and eNOS, as well as myocardial NO content when treated with 1 µM fasudil and IPoC alone. The inhibition of Rho‑kinase by fasudil was able to restore the cardioprotection of IPoC in the hypercholesterolemic rat heart. The underlying mechanisms involved in this process appear to be mediated by the activation of the PI3K/Akt/eNOS signal pathway and an increase in the myocardial NO content.
authors.affiliation: Department of Cardiology, The First Affiliated Hospital of China Medical University, Shenyang, Liaoning 110001, P.R. China.
authors.forename: Nan
authors.initials: N
authors.lastname: Wu
authors.affiliation: Department of Cardiology, The First Affiliated Hospital of China Medical University, Shenyang, Liaoning 110001, P.R. China.
authors.forename: Wenna
authors.initials: W
authors.lastname: Li
authors.affiliation: Department of Cardiology, The First Affiliated Hospital of China Medical University, Shenyang, Liaoning 110001, P.R. China.
authors.forename: Wenqi
authors.initials: W
authors.lastname: Shu
authors.affiliation: Department of Cardiology, The First Affiliated Hospital of China Medical University, Shenyang, Liaoning 110001, P.R. China.
authors.forename: Yan
authors.initials: Y
authors.lastname: Lv
authors.affiliation: Department of Cardiology, The First Affiliated Hospital of China Medical University, Shenyang, Liaoning 110001, P.R. China.
authors.forename: Dalin
authors.initials: D
authors.lastname: Jia
mesh_terms: D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine / Q000031:analogs & derivatives* / Q000494:pharmacology; D000730:Androstadienes / Q000494:pharmacology; D000818:Animals; D017209:Apoptosis; D002784:Cholesterol / Q000097:blood; D003331:Coronary Vessels / Q000187:drug effects / Q000503:physiopathology; D006937:Hypercholesterolemia / Q000097:blood / Q000150:complications; D057775:Ischemic Postconditioning; D008297:Male; D009203:Myocardial Infarction / Q000150:complications / Q000628:therapy*; D015428:Myocardial Reperfusion Injury / Q000209:etiology / Q000378:metabolism / Q000517:prevention & control*; D009206:Myocardium / Q000378:metabolism / Q000473:pathology; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D009569:Nitric Oxide / Q000378:metabolism; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D017208:Rats, Wistar; D000077191:Wortmannin; D054460:rho-Associated Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: D000730:Androstadienes; D047428:Protein Kinase Inhibitors; D009569:Nitric Oxide; D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine; D002784:Cholesterol; D052250:Nitric Oxide Synthase Type III; C496316:Nos3 protein, rat; D051057:Proto-Oncogene Proteins c-akt; D054460:rho-Associated Kinases; C049347:fasudil; D019331:NG-Nitroarginine Methyl Ester; D000077191:Wortmannin