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      S-Glutathiolation by peroxynitrite activates SERCA during arterial relaxation by nitric oxide.

      Nature medicine
      Animals, Arteriosclerosis, metabolism, Calcium, Calcium-Transporting ATPases, genetics, Cells, Cultured, Chromatography, High Pressure Liquid, DNA Primers, Glutathione, Humans, Immunoprecipitation, Mass Spectrometry, Mice, Mice, Transgenic, Muscle, Smooth, Vascular, Mutagenesis, Mutation, Nitric Oxide, Peroxynitrous Acid, Sarcoplasmic Reticulum Calcium-Transporting ATPases

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          Abstract

          Nitric oxide (NO) physiologically stimulates the sarco/endoplasmic reticulum calcium (Ca(2+)) ATPase (SERCA) to decrease intracellular Ca(2+) 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 Ca(2+)-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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