K. Shinmura et al., Cyclooxygenase-2 mediates the cardioprotective effects of the late phase of ischemic preconditioning in conscious rabbits, P NAS US, 97(18), 2000, pp. 10197-10202
Citations number
41
Language
INGLESE
art.tipo
Article
Categorie Soggetti
Multidisciplinary
Journal title
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
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.