title: Preemptive conditioning of the swine heart by H11 kinase/Hsp22 provides cardiac protection through inducible nitric oxide synthase.
abstract: The second window of ischemic preconditioning (SWOP) provides maximal protection against ischemia through regulation of the inducible nitric oxide synthase (iNOS), yet its application is limited by the inconvenience of the preliminary ischemic stimulus required for prophylaxis. Overexpression of H11 kinase/Hsp22 (Hsp22) in a transgenic mouse model provides cardioprotection against ischemia that is equivalent to that conferred by SWOP. We hypothesized that short-term, prophylactic overexpression of Hsp22 would offer an alternative to SWOP in reducing ischemic damage through a nitric oxide (NO)-dependent mechanism. Adeno-mediated overexpression of Hsp22 was achieved in the area at risk of the left circumflex (Cx) coronary artery in chronically instrumented swine and compared with LacZ controls (n = 5/group). Hsp22-injected myocardium showed an average fourfold increase in Hsp22 protein expression compared with controls and a doubling in iNOS expression (both P < 0.05). Four days after ischemia-reperfusion, regional wall thickening was reduced by 58 ± 2% in the Hsp22 group vs. 82 ± 7% in the LacZ group, and Hsp22 reduced infarct size by 40% (both P < 0.05 vs. LacZ). Treatment with the NOS inhibitor N(G)-nitro-L-arginine (L-NNA) before ischemia suppressed the protection induced by Hsp22. In isolated cardiomyocytes, Hsp22 increased iNOS expression through the transcription factors NF-κB and STAT, the same effectors activated by SWOP, and reduced by 60% H(2)O(2)-mediated apoptosis, which was also abolished by NOS inhibitors. Therefore, short-term, prophylactic conditioning by Hsp22 provides NO-dependent cardioprotection that reproduces the signaling of SWOP, placing Hsp22 as a potential alternative for preemptive treatment of myocardial ischemia.
authors.affiliation: Cardiovascular Research Institute, Department of Cell Biology and Molecular Medicine, University of Medicine and Dentistry of New Jersey, New Jersey Medical School, Newark, 07103, USA.
authors.forename: Li
authors.initials: L
authors.lastname: Chen
authors.forename: Paulo
authors.initials: P
authors.lastname: Lizano
authors.forename: Xin
authors.initials: X
authors.lastname: Zhao
authors.forename: Xiangzhen
authors.initials: X
authors.lastname: Sui
authors.forename: Sunil K
authors.initials: SK
authors.lastname: Dhar
authors.forename: You-Tang
authors.initials: YT
authors.lastname: Shen
authors.forename: Dorothy E
authors.initials: DE
authors.lastname: Vatner
authors.forename: Stephen F
authors.initials: SF
authors.lastname: Vatner
authors.forename: Christophe
authors.initials: C
authors.lastname: Depre
mesh_terms: D000818:Animals; D030801:Animals, Genetically Modified; D002478:Cells, Cultured; D003331:Coronary Vessels / Q000187:drug effects / Q000378:metabolism / Q000502:physiology; D006360:Heat-Shock Proteins / Q000096:biosynthesis* / Q000235:genetics; D019157:Ischemic Preconditioning, Myocardial / Q000379:methods*; D051379:Mice; D017202:Myocardial Ischemia / Q000201:enzymology / Q000517:prevention & control*; D009206:Myocardium / Q000201:enzymology*; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000201:enzymology / Q000502:physiology; D016328:NF-kappa B / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II / Q000096:biosynthesis*; D019335:Nitroarginine / Q000494:pharmacology; D017346:Protein Serine-Threonine Kinases / Q000096:biosynthesis* / Q000235:genetics; D013552:Swine
chemical_list: D006360:Heat-Shock Proteins; D016328:NF-kappa B; D019335:Nitroarginine; D052247:Nitric Oxide Synthase Type II; D017346:Protein Serine-Threonine Kinases