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Am J Physiol Heart Circ Physiol (February 26, 2004). doi:10.1152/ajpheart.00037.2004
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Submitted on January 15, 2004
Accepted on February 23, 2004

Cardioprotection by Chronic Estrogen or Superoxide Dismutase Mimetic Treatment in the Aged Female Rat

Yi Xu1, Stephen J. Armstrong1, Ivan A. Arenas1, Daniel J. Pehowich2, and Sandra T. Davidge1*

1 Department of Obstetrics/Gynecology and Physiology, University of Alberta, Edmonton, AB, Canada
2 Department of Dentistry, University of Alberta, Edmonton, AB, Canada

* To whom correspondence should be addressed. E-mail: sandra.davidge{at}ualberta.ca.

Aging and estrogen deficiency increase the risk for developing cardiovascular disease (CVD). Oxidative stress has also been implicated in the pathophysiology of CVD, and in ischemia-reperfusion (I/R) injury. We tested the hypothesis that either chronic in vivo estrogen treatment or superoxide inhibition with the SOD mimetic, EUK-8, improves cardiac functional recovery after I/R in the aged female rat. Sprague Dawley rats (12-14 months) were used: Intact (n=6), Ovariectomized + Placebo (OVX, n=6), OVX + EUK-8 (EUK-8, 3mg/kg, n=6), OVX + Estrogen (E2, 1.5mg/pellet, 60 days release, n=6). Perfused isolated hearts were subjected to global ischemia (25 minutes) followed by reperfusion (40 minutes). Functional recovery after I/R and myocardial expression of NADPH oxidase (p22, p67, and gp91phox), iNOS, eNOS, and SOD1 protein expression, as well as nitrotyrosine levels (as a marker for peroxynitrite) were assessed. Compared to OVX, both EUK-8 and E2 markedly improved functional recovery following I/R that was associated with a decrease in NADPH oxidase expression and nitrotyrosine staining. However, E2 increased iNOS expression, while EUK-8 had little effect. There were no significant changes in eNOS and SOD1 expression among the groups. These results indicate that EUK-8 and E2 improved cardiac recovery following I/R. Given the controversy surrounding hormone replacement therapy, EUK-8 may be an alternative to estrogen in protecting those at risk for myocardial ischemia in the aging population.




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