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Am J Physiol Heart Circ Physiol 287: H165-H171, 2004. First published February 26, 2004; doi:10.1152/ajpheart.00037.2004
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Cardioprotection by chronic estrogen or superoxide dismutase mimetic treatment in the aged female rat

Yi Xu,1 Stephen J. Armstrong,1 Ivan A. Arenas,1 Daniel J. Pehowich,2 and Sandra T. Davidge1

1Departments of Obstetrics/Gynecology and Physiology and 2Department of Dentistry, Perinatal Research Centre, University of Alberta, Edmonton, Alberta, Canada T6G 2S2

Submitted 15 January 2004 ; accepted in final form 23 February 2004

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 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 mo) were used as follows: intact (n = 6), ovariectomized + placebo (OVX, n = 6), OVX + EUK-8 (EUK-8, 3 mg/kg, n = 6), and OVX + estrogen (1.5 mg/pellet, 60 days release, n = 6). Perfused isolated hearts were subjected to global ischemia (25 min) followed by reperfusion (40 min). Functional recovery after I/R and myocardial protein expression of NADPH oxidase (p22, p67, and gp91phox), inducible nitric oxide synthase (NOS), endothelial NOS, and SOD1, as well as nitrotyrosine levels (as a marker for peroxynitrite), were assessed. Compared with OVX, EUK-8 and estrogen markedly improved functional recovery after I/R, which was associated with a decrease in NADPH oxidase expression and nitrotyrosine staining. However, estrogen increased inducible NOS expression, whereas EUK-8 had little effect. There were no significant changes in endothelial NOS and SOD1 expression among the groups. These results indicate that EUK-8 and estrogen improved cardiac recovery after 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.

aging; ischemia; reperfusion; oxygen radicals


Address for reprint requests and other correspondence: S. T. Davidge, Perinatal Research Centre, 232 HMRC, Univ. of Alberta, Edmonton, Alberta, Canada T6G 2S2 (E-mail: sandra.davidge{at}ualberta.ca).




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