Nature Medicine10, 1200 - 1207 (2004)
Published online: 17 October 2004; | doi:10.1038/nm1119
S-Glutathiolation by peroxynitrite activates SERCA during arterial relaxation by nitric oxide
Takeshi Adachi1, Robert M Weisbrod1, David R Pimentel1, Jia Ying1, Victor S Sharov2, Christian Schöneich2
& Richard A Cohen1
1
Vascular and Myocardial Biology Units, Whitaker Cardiovascular Institute, Boston University Medical Center, X707, 650 Albany Street, Boston, Massachusetts 02118-2393, USA.
2
Department of Pharmaceutical Chemistry, University of Kansas School of Pharmacy, 2095 Constant Avenue, Lawrence, Kansas, 66047, USA.
Nitric oxide (NO) physiologically stimulates the sarco/endoplasmic reticulum calcium (Ca2+) ATPase (SERCA) to decrease intracellular Ca2+ concentration and relax cardiac, skeletal and vascular smooth muscle. Here, we show that NO-derived peroxynitrite (ONOO-) directly increases SERCA activity by S-glutathiolation and that this modification of SERCA is blocked by irreversible oxidation of the relevant cysteine thiols during atherosclerosis. Purified SERCA was S-glutathiolated by ONOO- and the increase in Ca2+-uptake activity of SERCA reconstituted in phospholipid vesicles required the presence of glutathione. Mutation of the SERCA-reactive Cys674 to serine abolished these effects. Because superoxide scavengers decreased S-glutathiolation of SERCA and arterial relaxation by NO, ONOO- is implicated as the intracellular mediator. NO-dependent relaxation as well as S-glutathiolation and activation of SERCA were decreased by atherosclerosis and Cys674 was found to be oxidized to sulfonic acid. Thus, irreversible oxidation of key thiol(s) in disease impairs NO-induced relaxation by preventing reversible S-glutathiolation and activation of SERCA by NO/ONOO-.
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