Published Online
on November 20, 2006

A more recent version of this article appeared on December 12, 2006

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Submitted on April 4, 2006
Revised on September 29, 2006
Accepted on October 6, 2006

Statins Activate AMP-Activated Protein Kinase In Vitro and In Vivo

Wei Sun MD, Tzong-Shyuan Lee DVM, PhD, Minjia Zhu BS, Chunang Gu MS, Yinsheng Wang PhD, Yi Zhu MD, and John Y-J. Shyy PhD^*

From the Division of Biomedical Sciences (W.S., T.-S.L., Y.Z., J.Y.-J.S.), Environmental Toxicology Graduate Program (C.G.), and Department of Chemistry (Y.W.), University of California, Riverside; and Department of Physiology (M.Z., Y.Z.), Key Laboratory of Molecular Cardiovascular Sciences of Education Ministry, Health Science Center, Peking University, Beijing, China.

^* To whom correspondence should be addressed. E-mail: john.shyy{at}ucr.edu.

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.

Methods and 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.

Key words: statins • angiogenesis • aorta • endothelium • nitric oxide • nitric oxide synthase • myocardium

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