title: Cyclooxygenase-2 mediates the cardioprotective effects of the late phase of ischemic preconditioning in conscious rabbits.
abstract: We examined the role of cyclooxygenase-2 (COX-2) in the late phase of ischemic preconditioning (PC). A total of 176 conscious rabbits were used. Ischemic PC (six cycles of 4-min coronary occlusions/4-min reperfusions) resulted in a rapid increase in myocardial COX-2 mRNA levels (+231 +/- 64% at 1 h; RNase protection assay) followed 24 h later by an increase in COX-2 protein expression (+216 +/- 79%; Western blotting) and in the myocardial content of prostaglandin (PG)E(2) and 6-keto-PGF(1alpha) (+250 +/- 85% and +259 +/- 107%, respectively; enzyme immunoassay). Administration of two unrelated COX-2 selective inhibitors (NS-398 and celecoxib) 24 h after ischemic PC abolished the ischemic PC-induced increase in tissue levels of PGE(2) and 6-keto-PGF(1alpha). The same doses of NS-398 and celecoxib, given 24 h after ischemic PC, completely blocked the cardioprotective effects of late PC against both myocardial stunning and myocardial infarction, indicating that COX-2 activity is necessary for this phenomenon to occur. Neither NS-398 nor celecoxib lowered PGE(2) or 6-keto-PGF(1alpha) levels in the nonischemic region of preconditioned rabbits, indicating that constitutive COX-1 activity was unaffected. Taken together, these results demonstrate that, in conscious rabbits, up-regulation of COX-2 plays an essential role in the cardioprotection afforded by the late phase of ischemic PC. Therefore, this study identifies COX-2 as a cardioprotective protein. The analysis of arachidonic acid metabolites strongly points to PGE(2) and/or PGI(2) as the likely effectors of COX-2-dependent protection. The recognition that COX-2 mediates the antistunning and antiinfarct effects of late PC impels a reassessment of current views regarding this enzyme, which is generally regarded as detrimental.
authors.affiliation: The Experimental Research Laboratory, Division of Cardiology, University of Louisville, and Jewish Hospital Heart and Lung Institute, Louisville, KY 40292, USA.
authors.forename: K
authors.initials: K
authors.lastname: Shinmura
authors.forename: X L
authors.initials: XL
authors.lastname: Tang
authors.forename: Y
authors.initials: Y
authors.lastname: Wang
authors.forename: Y T
authors.initials: YT
authors.lastname: Xuan
authors.forename: S Q
authors.initials: SQ
authors.lastname: Liu
authors.forename: H
authors.initials: H
authors.lastname: Takano
authors.forename: A
authors.initials: A
authors.lastname: Bhatnagar
authors.forename: R
authors.initials: R
authors.lastname: Bolli
mesh_terms: D015121:6-Ketoprostaglandin F1 alpha / Q000378:metabolism; D000818:Animals; D000068579:Celecoxib; D051546:Cyclooxygenase 2; D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology; D015237:Dinoprost / Q000378:metabolism; D015971:Gene Expression Regulation, Enzymologic; D019194:Ischemic Preconditioning; D007527:Isoenzymes / Q000235:genetics* / Q000378:metabolism*; D008297:Male; D009203:Myocardial Infarction / Q000201:enzymology / Q000517:prevention & control*; D017202:Myocardial Ischemia / Q000201:enzymology / Q000503:physiopathology*; D017682:Myocardial Stunning / Q000201:enzymology / Q000517:prevention & control*; D009206:Myocardium / Q000378:metabolism; D009578:Nitrobenzenes / Q000494:pharmacology; D011451:Prostaglandin-Endoperoxide Synthases / Q000235:genetics* / Q000378:metabolism*; D011458:Prostaglandins E / Q000378:metabolism; D011720:Pyrazoles; D011817:Rabbits; D013449:Sulfonamides / Q000494:pharmacology; D014158:Transcription, Genetic
chemical_list: D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors; D007527:Isoenzymes; D009578:Nitrobenzenes; D011458:Prostaglandins E; D011720:Pyrazoles; D013449:Sulfonamides; C080955:N-(2-cyclohexyloxy-4-nitrophenyl)methanesulfonamide; D015121:6-Ketoprostaglandin F1 alpha; D015237:Dinoprost; D051546:Cyclooxygenase 2; D011451:Prostaglandin-Endoperoxide Synthases; D000068579:Celecoxib