Cyclooxygenase-2 mediates the cardioprotective effects of the late phase of ischemic preconditioning in conscious rabbits

We examined the role of cyclooxygenase-2 (COX-2) in the late phase of ische mic preconditioning (PC). A total of 176 conscious rabbits were used. Ische mic: PC (six cycles of 4-min coronary occlusions/4-min reperfusions) result ed 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 prote in expression (+216 +/- 79%; Western blotting) and in the myocardial conten t of prostaglandin (PG)E-2 and 6-keto-PGF(1 alpha) (+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 a bolished the ischemic PC-induced increase in tissue levels of PGE(2) and 6- keto-PGF(1 alpha). The same doses of NS-398 and celecoxib, given 24 h after ischemic PC, completely blocked the cardioprotective effects of late PC ag ainst both myocardial stunning and myocardial infarction, indicating that C OX-2 activity is necessary for this phenomenon to occur, Neither NS-398 nor celecoxib lowered PGE(2) or 6-keto-PGF(1 alpha) levels in the nonischemic region of preconditioned rabbits, indicating that constitutive COX-1 activi ty was unaffected. Taken together, these results demonstrate that, in consc ious rabbits, up-regulation of COX-2 plays an essential role in the cardiop rotection 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 PGl(2) as the likely eff ecters of COX-2-dependent protection. The recognition that COX-2 mediates t he antistunning and antiinfarct effects of late PC impels a reassessment of current views regarding this enzyme, which is generally regarded as detrim ental.