Reactive nitrogen species is required for the activation of the AMP-activated protein kinase by statin in vivo

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Abstract

The AMP-activated protein kinase (AMPK) is reported to mediate the beneficial effects of statin on the vascular functions, but the biochemical mechanisms are incompletely understood. The aim of the study was to determine how statin activates AMPK. Exposure of confluent bovine aortic endothelial cells to simvastatin (statin) dose-dependently increased phosphorylation of AMPK at Thr172 and activities of AMPK, which was in parallel with increased detection of both LKB1 phosphorylation at Ser428 and LKB1 nuclear export. Furthermore, statin treatment was shown to increase protein kinase C (PKC)-ζ activity and PKC-ζ phosphorylation at Thr410/ Thr403. Consistently, inhibition of PKC-ζ either by pharmacological or genetic manipulations abolished statin-enhanced LKB1 phosphorylation at Ser428, blocked LKB1 nucleus export, and prevented the subsequent activation of AMPK. Similarly, in vivo transfection of PKC-ζ-specific small interfering RNA in C57BL/6J mice significantly attenuated statin-enhanced phosphorylation of AMPK-Thr172, acetyl-CoA carboxylase (ACC)-Ser79, and LKB1-Ser428. In addition, statin significantly increased reactive oxygen species, whereas preincubation of mito-TEMPOL, a superoxide dismutase mimetic, abolished statin-enhanced phosphorylation of both AMPK-Thr172 and ACC-Ser79. Finally, in vivo administration of statin increased 3-nitrotyrosine and the phosphorylation of AMPK and ACC in C57BL/6J mice but not in mice deficient in endothelial nitric-oxide synthase. Taken together, our data suggest that AMPK activation by statin is peroxynitrite-mediated but PKC-ζ-dependent. © 2008 by The American Society for Biochemistry and Molecular Biology, Inc.

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Hyoung, C. C., Song, P., Xie, Z., Wu, Y., Xu, J., Zhang, M., … Zou, M. H. (2008). Reactive nitrogen species is required for the activation of the AMP-activated protein kinase by statin in vivo. Journal of Biological Chemistry, 283(29), 20186–20197. https://doi.org/10.1074/jbc.M803020200

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