Published online before print January 5, 2006, doi: 10.1161/01.RES.0000202707.79018.0a
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Submitted on October 26, 2004
Revised on December 12, 2005
Accepted on December 21, 2005
Hypercontractile Female Hearts Exhibit Increased S-Nitrosylation of the L-Type Ca2+ Channel 
1 Subunit and Reduced Ischemia-Reperfusion Injury
Junhui Sun ;
From the National Institute of Environmental Health Sciences (J.S., E.M.), Research Triangle Park, NC; Department of Physiology (E.P., K.S.G., D.M.B.), Stritch School of Medicine, Loyola University Chicago, Maywood, Ill; and Department of Pathology (C.S.), Duke University Medical Center, Durham, NC.
* To whom correspondence should be addressed. E-mail: murphy1{at}niehs.nih.gov.
Mechanisms underlying gender differences in cardiovascular disease are poorly understood. We found previously that, under hypercontractile conditions, female hearts exhibit significantly less ischemia-reperfusion injury than males. Here we show that male wild-type (WT) mouse hearts pretreated with 10 nmol/L isoproterenol before ischemia exhibited increased injury versus female hearts, but this relative protection in females was absent in eNOS-/- and nNOS-/- hearts. In isoproterenol-treated female versus male hearts, there was also more endothelial NO synthase (eNOS) associated with cardiomyocyte caveolin-3, and more neuronal NOS (nNOS) translocation to caveolin-3 during ischemia-reperfusion. S-nitrosothiol (SNO) formation was increased in isoproterenol-treated ischemic-reperfused hearts in all mouse genotypes, but only in WT mice was SNO content significantly higher in females than males. Using the biotin switch method, we identified the L-type Ca2+ channel 
1 subunit as the predominant S-nitrosylated protein in membrane fractions, and following isoproterenol and ischemia-reperfusion male/female differences in SNO were seen only in WT hearts, but not in constitutive NOS-/- genotypes. The isoproterenol-induced increase in L-type Ca2+ current (ICa) was smaller in females versus in males, but NOS blockade increased ICa in females. This gender difference in ICa in isoproterenol-treated myocytes (and abolition on NOS inhibition) was mirrored exactly in Ca2+ transients and SR Ca2+ contents. In conclusion, these data suggest that eNOS and nNOS both play roles in the gender differences observed in ischemia-reperfusion injury under adrenergic stimulation, and also demonstrate increased S-nitrosylation of the L-type Ca2+ channels in female cardiomyocytes.
Key words: ischemia • gender • endothelial nitric oxide synthase • neuronal nitric oxide synthase • S-nitrosylation • L-type Ca2+ channel
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