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MEMBRANE TRANSPORTERS, ION CHANNELS, AND PUMPS

Angiotensin II inhibits the Na⁺-K⁺ pump via PKC-dependent activation of NADPH oxidase

¹North Shore Cardiac Research Group, Kolling Institute, University of Sydney, Sydney, Australia; and ²Department of Cardiology, Royal North Shore Hospital, Sydney, Australia

Submitted 19 December 2008 ; accepted in final form 3 February 2009

The sarcolemmal Na⁺-K⁺ pump, pivotal in cardiac myocyte function, is inhibited by angiotensin II (ANG II). Since ANG II activates NADPH oxidase, we tested the hypothesis that NADPH oxidase mediates the pump inhibition. Exposure to 100 nmol/l ANG II increased superoxide-sensitive fluorescence of isolated rabbit ventricular myocytes. The increase was abolished by pegylated superoxide dismutase (SOD), by the NADPH oxidase inhibitor apocynin, and by myristolated inhibitory peptide to -protein kinase C (PKC), previously implicated in ANG II-induced Na⁺-K⁺ pump inhibition. A role for PKC was also supported by an ANG II-induced increase in coimmunoprecipitation of PKC with the receptor for the activated kinase and with the cytosolic p47^phox subunit of NADPH oxidase. ANG II decreased electrogenic Na⁺-K⁺ pump current in voltage-clamped myocytes. The decrease was abolished by SOD, by the gp91ds inhibitory peptide that blocks assembly and activation of NADPH oxidase, and by PKC inhibitory peptide. Since colocalization should facilitate NADPH oxidase-dependent regulation of the Na⁺-K⁺ pump, we examined whether there is physical association between the pump subunits and NADPH oxidase. The ₁-subunit coimmunoprecipitated with caveolin 3 and with membrane-associated p22^phox and cytosolic p47^phox NADPH oxidase subunits at baseline. ANG II had no effect on ₁/caveolin 3 or ₁/p22^phox interaction, but it increased ₁/p47^phox coimmunoprecipitation. We conclude that ANG II inhibits the Na⁺-K⁺ pump via PKC-dependent NADPH oxidase activation.

reduced nicotinamide adenine dinucleotide phosphatase oxidase; oxidant signaling; glutathionylation; protein kinase C; Na⁺-K⁺-ATPase

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