Statins activate AMP-activated protein kinase in vitro and in vivo.
BACKGROUND
Statins exert pleiotropic effects on the cardiovascular system, in part through an increase in nitric oxide (NO) bioavailability. AMP-activated protein kinase (AMPK) plays a central role in controlling energy and metabolism homeostasis in various organs. We therefore studied whether statins can activate AMPK, and if so, whether the activated AMPK regulates nitric oxide (NO) production and angiogenesis mediated by endothelial NO synthase, a substrate of AMPK in vascular endothelial cells.


RESULTS
Western blotting of protein extracts from human umbilical vein endothelial cells treated with atorvastatin revealed increased phosphorylation of AMPK at Thr-172 in a time- and dose-dependent manner. The AMPK activity, assessed by SAMS assay, was also increased accordingly. The phosphorylation of acetyl-CoA carboxylase at Ser-79 and of endothelial NO synthase at Ser-1177, 2 putative downstream targets of AMPK, was inhibited by an adenovirus that expressed a dominant-negative mutant of AMPK (Ad-AMPK-DN) and compound C, an AMPK antagonist. The positive effects of atorvastatin, including NO production, cGMP accumulation, and in vitro angiogenesis in Matrigel, were all blocked by Ad-AMPK-DN. Mice given atorvastatin through gastric gavage showed increased AMPK, acetyl-CoA carboxylase, and endothelial NO synthase phosphorylation in mouse aorta and myocardium.


CONCLUSIONS
Statins can rapidly activate AMPK via increased Thr-172 phosphorylation in vitro and in vivo. Such phosphorylation results in endothelial NO synthase activation, which provides a novel explanation for the pleiotropic effects of statins that benefit the cardiovascular system.
Sun
Wei
W
Division of Biomedical Sciences, University of California, Riverside, Riverside, CA 92521-0121, USA.
Lee
Tzong-Shyuan
TS
Zhu
Minjia
M
Gu
Chunang
C
Wang
Yinsheng
Y
Zhu
Yi
Y
Shyy
John Y-J
JY
D055372:AMP-Activated Protein Kinases; D000103:Acetyl-CoA Carboxylase / Q000378:metabolism; D000069059:Atorvastatin; D002478:Cells, Cultured; D042783:Endothelial Cells / Q000187:drug effects / Q000378:metabolism; D006538:Heptanoic Acids / Q000494:pharmacology; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology*; D009097:Multienzyme Complexes / Q000378:metabolism*; D018919:Neovascularization, Physiologic / Q000187:drug effects; D009569:Nitric Oxide / Q000096:biosynthesis; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D011758:Pyrroles / Q000494:pharmacology
D006538:Heptanoic Acids; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D009097:Multienzyme Complexes; D011758:Pyrroles; D009569:Nitric Oxide; D000069059:Atorvastatin; D052250:Nitric Oxide Synthase Type III; D017346:Protein Serine-Threonine Kinases; D055372:AMP-Activated Protein Kinases; D000103:Acetyl-CoA Carboxylase