Title |
Stimulation of the cardiac myocyte Na+-K+ pump due to reversal of its constitutive oxidative inhibition
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Published in |
American Journal of Physiology: Cell Physiology, June 2015
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DOI | 10.1152/ajpcell.00392.2014 |
Pubmed ID | |
Authors |
Karin K M Chia, Chia-Chi Liu, Elisha J Hamilton, Alvaro Garcia, Natasha A Fry, William Hannam, Gemma A Figtree, Helge H Rasmussen |
Abstract |
Protein kinase C can activate NADPH oxidase and induce glutathionylation of the β1 Na(+)-K(+) pump subunit, inhibiting activity of the catalytic α subunit. To examine if signaling of nitric oxide-induced soluble guanylyl cyclase (sGC)/cGMP/protein kinase G can cause Na(+)-K(+) pump stimulation by counteracting PKC/NADPH oxidase-dependent inhibition cardiac myocytes were exposed to Ang II to activate NADPH oxidase and inhibit Na(+)-K(+) pump current (Ip). Co-exposure to 3-(5'-hydroxymethyl-2'-furyl)-1-benzylindazole (YC-1) to stimulate sGC prevented the decrease of Ip. Prevention of the decrease was abolished by inhibition of protein phosphatases 2A (PP2A) but not by inhibition of PP1 and it was reproduced by an activator of PP2A. Consistent with a reciprocal relationship between β1 Na(+)-K(+) pump subunit glutathionylation and pump activity, YC-1 decreased Ang II-induced β1 subunit glutathionylation. The decrease induced by YC-1 was abolished by a PP2A inhibitor. YC-1 decreased phosphorylation of the cytosolic p47phox NADPH oxidase subunit and its co-immunoprecipitation with the membranous p22phox subunit and it decreased O2 (●-)-sensitive dihydroethidium fluorescence of myocytes. Addition of recombinant PP2A to myocyte lysate decreased phosphorylation of p47(phox) indicating the subunit could be a substrate for PP2A. Effects of YC-1 to decrease co-immunoprecipitation of p22phox and p47(phox) NADPH oxidase subunits and decrease β1 Na(+)-K(+) pump subunit glutathionylation were reproduced by activation of nitric oxide-dependent receptor signaling. We conclude that sGC activation in cardiac myocytes causes a PP2A-dependent decrease in NADPH oxidase activity and a decrease in β1 pump subunit glutathionylation. This could account for pump stimulation with neurohormonal oxidative stress expected in vivo. |
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