Published online before print January 5, 2006, doi: 10.1161/01.RES.0000202707.79018.0a
© 2006 American Heart Association, Inc.
Integrative Physiology |
Hypercontractile Female Hearts Exhibit Increased S-Nitrosylation of the L-Type Ca2+ Channel 
1 Subunit and Reduced Ischemia/Reperfusion Injury
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.
Correspondence to Dr Elizabeth Murphy, National Institute of Environmental Health Sciences, Laboratory of Signal Transduction, MD 2-03, Room F279, 111 TW Alexander Dr, Research Triangle Park, NC 27709. 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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