期刊
JOURNAL OF BIOLOGICAL CHEMISTRY
卷 283, 期 29, 页码 20186-20197出版社
AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC
DOI: 10.1074/jbc.M803020200
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资金
- NHLBI NIH HHS [R01 HL110488, HL 080499, R01 HL079584, HL 07439, R01 HL074399, HL 089220, HL 079584, R01 HL080499, R01 HL096032, R01 HL105157] Funding Source: Medline
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 Thr(172) and activities of AMPK, which was in parallel with increased detection of both LKB1 phosphorylation at Ser(428) and LKB1 nuclear export. Furthermore, statin treatment was shown to increase protein kinase C (PKC)-zeta activity and PKC-zeta phosphorylation at Thr(410)/Thr(403). Consistently, inhibition of PKC-zeta 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-zeta-specific small interfering RNA in C57BL/6J mice significantly attenuated statin-enhanced phosphorylation of AMPK-Thr(172), acetyl-CoA carboxylase (ACC)-Ser(79), and LKB1-Ser(428). In addition, statin significantly increased reactive oxygen species, whereas preincubation of mito-TEMPOL, a superoxide dismutase mimetic, abolished statin-enhanced phosphorylation of both AMPK-Thr(172) and ACC-Ser(79). 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 thatAMPKactivation by statin is peroxynitrite-mediated but PKC-zeta-dependent.
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