Hypercontractile female hearts exhibit increased S-nitrosylation of the L-type Ca2+ channel α1 subunit and reduced ischemia/reperfusion injury

Junhui Sun, Eckard Picht, Kenneth S Ginsburg, Donald M Bers, Charles Steenbergen, Elizabeth Murphy

Research output: Contribution to journalArticle

222 Scopus citations

Abstract

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 α1 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 Ca 2+ 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 Ca 2+ 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.

Original languageEnglish (US)
Pages (from-to)403-411
Number of pages9
JournalCirculation Research
Volume98
Issue number3
DOIs
StatePublished - Feb 2006
Externally publishedYes

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Keywords

  • Endothelial nitric oxide synthase
  • Gender
  • Ischemia
  • L-type Ca channel
  • Neuronal nitric oxide synthase
  • S-nitrosylation

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine

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