S-Glutathiolation by peroxynitrite activates SERCA during arterial relaxation by nitric oxide
T Adachi, RM Weisbrod, DR Pimentel, J Ying… - Nature medicine, 2004 - nature.com
T Adachi, RM Weisbrod, DR Pimentel, J Ying, VS Sharov, C Schöneich, RA Cohen
Nature medicine, 2004•nature.comNitric 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 …
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 …
Abstract
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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