Estrogen protects the heart from ischemia-reperfusion injury via COX-2-derived PGI2.
There is an accumulating body of data to suggest that estrogen mediates its cardioprotective effects via cyclooxygenase activation and synthesis of prostaglandins (PG), specifically PGI2. We hypothesized that inhibition of COX-2 would prevent estrogen's cardioprotective effects after myocardial ischemia-reperfusion. Acute treatment with 17beta-estradiol (E2; 20 microg/rabbit) increased COX-2 protein expression and activity in the myocardium. To determine the effects of COX-2 inhibition on infarct size after E2 treatment, New Zealand white rabbits were anesthetized and administered the COX-2 inhibitor nimesulide (5 mg/kg) or vehicle intravenously 30 minutes before an intravenous injection of E2. Thirty minutes after estrogen treatment, the coronary artery was occluded for 30 minutes followed by 4 hours of reperfusion. E2 significantly decreased infarct size as a percent of area at risk when compared to vehicle (18.9 +/- 3.1 versus 47.0 +/- 4.1; P < 0.001). Pretreatment with nimesulide nullified the infarct size sparing effect of E2 (55.8 +/- 5.6). Treatment with the PGI2 receptor antagonist RO3244794 also abolished the protective effects of E2 (45.3 +/- 4.5). The results indicate that estrogen protects the myocardium from ischemia-reperfusion injury through increased production of COX-2-derived PGI2. The data indicate that selective COX-2 inhibitors might counteract the potential cytoprotective effects of estrogen in premenopausal or postmenopausal women.
Booth
Erin Anne
EA
Department of Pharmacology, University of Michigan Medical School, Ann Arbor, Michigan 48109-5632, USA. boothea@umich.edu
Flint
RaShonda Renee
RR
Lucas
Kathryn Louise
KL
Knittel
Andrea Kathleen
AK
Lucchesi
Benedict R
BR
D000818:Animals; D001572:Benzofurans / Q000494:pharmacology; D051546:Cyclooxygenase 2 / Q000187:drug effects* / Q000378:metabolism; D052246:Cyclooxygenase 2 Inhibitors / Q000494:pharmacology; D011464:Epoprostenol / Q000378:metabolism*; D004958:Estradiol / Q000494:pharmacology*; D004967:Estrogens / Q000494:pharmacology; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D008297:Male; D015428:Myocardial Reperfusion Injury / Q000517:prevention & control*; D011422:Propionates / Q000494:pharmacology; D011817:Rabbits; D013449:Sulfonamides / Q000494:pharmacology
D001572:Benzofurans; D052246:Cyclooxygenase 2 Inhibitors; D004967:Estrogens; D011422:Propionates; C515593:RO3244794; D013449:Sulfonamides; D004958:Estradiol; D011464:Epoprostenol; D051546:Cyclooxygenase 2; C012655:nimesulide