Published online before print March 5, 2009, doi: 10.1161/CIRCRESAHA.108.188441
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Submitted on December 19, 2008
Revised on February 19, 2009
Accepted on February 23, 2009
Nitroxyl Activates SERCA in Cardiac Myocytes via Glutathiolation of Cysteine 674
Steve Lancel ;
From the Cardiovascular Medicine Section, Department of Medicine, and the Myocardial and Vascular Biology Units, Boston University Medical Center, Mass.
* To whom correspondence should be addressed. E-mail: wilson.colucci{at}bmc.org.
Nitroxyl (HNO) exerts inotropic and lusitropic effects in myocardium, in part via activation of SERCA (sarcoplasmic reticulum calcium ATPase). To elucidate the molecular mechanism, adult rat ventricular myocytes were exposed to HNO derived from Angeli's salt. HNO increased the maximal rate of thapsigargin-sensitive Ca2+ uptake mediated by SERCA in sarcoplasmic vesicles and caused reversible oxidative modification of SERCA thiols. HNO increased the S-glutathiolation of SERCA, and adenoviral overexpression of glutaredoxin-1 prevented both the HNO-stimulated oxidative modification of SERCA and its activation, as did overexpression of a mutated SERCA in which cysteine 674 was replaced with serine. Thus, HNO increases the maximal activation of SERCA via S-glutathiolation at cysteine 674.
Key words: sarcoplasmic reticulum ATPase • SERCA • nitroxyl • glutathiolation • cardiac myocytes