Cardioprotection by chronic estrogen or superoxide dismutase mimetic treatment in the aged female rat.
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 gp91(phox)), 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.
Department of Obstetrics/Gynecology, Perinatal Research Centre, 232 HMRC, University of Alberta, Edmonton, Alberta, Canada T6G 2S2.
Yi
Y
Xu
Stephen J
SJ
Armstrong
Ivan A
IA
Arenas
Daniel J
DJ
Pehowich
Sandra T
ST
Davidge
D000375:Aging / Q000502:physiology*; D000818:Animals; D001835:Body Weight / Q000187:drug effects; D002316:Cardiotonic Agents / Q000494:pharmacology*; D004967:Estrogens / Q000494:pharmacology*; D005029:Ethylenediamines / Q000494:pharmacology*; D005260:Female; D006321:Heart / Q000033:anatomy & histology / Q000187:drug effects*; D006352:Heart Ventricles; D017202:Myocardial Ischemia / Q000473:pathology / Q000503:physiopathology*; D015428:Myocardial Reperfusion Injury / Q000473:pathology / Q000503:physiopathology*; D019255:NADPH Oxidases / Q000378:metabolism; D019001:Nitric Oxide Synthase / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II; D052250:Nitric Oxide Synthase Type III; D009929:Organ Size; D009942:Organometallic Compounds / Q000494:pharmacology*; D010052:Ovariectomy; D051381:Rats; D017207:Rats, Sprague-Dawley; D020127:Recovery of Function / Q000187:drug effects; D013482:Superoxide Dismutase / Q000494:pharmacology; D014443:Tyrosine / Q000031:analogs & derivatives* / Q000378:metabolism; D014599:Uterus / Q000033:anatomy & histology
D002316:Cardiotonic Agents; D004967:Estrogens; D005029:Ethylenediamines; D009942:Organometallic Compounds; C002744:3-nitrotyrosine; D014443:Tyrosine; C090577:N,N'-bis(salicylideneamino)ethane-manganese(II); D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; D052250:Nitric Oxide Synthase Type III; C496318:Nos2 protein, rat; C496316:Nos3 protein, rat; D013482:Superoxide Dismutase; D019255:NADPH Oxidases