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J Physiol Volume 581, Number 3, 1163-1171, June 15, 2007 DOI: 10.1113/jphysiol.2007.132589
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CARDIOVASCULAR

Activation of AMP kinase {alpha}1 subunit induces aortic vasorelaxation in mice

 Françoise Goirand1,2, Myriam Solar1,2, Yoni Athea1,3, Benoit Viollet4,5, Philippe Mateo1,3, Dominique Fortin1,3, Jocelyne Leclerc4,5, Jacqueline Hoerter1,3, Renée Ventura-Clapier1,3 and Anne Garnier1,3

1 Univ Paris-Sud, IFR-141, Châtenay-Malabry, France
2 INRA, UMR 1154, Châtenay-Malabry, France
3 INSERM, U 769, Châtenay-Malabry, France
4 Institut Cochin, Université Paris Descartes, CNRS (UMR 8104), Paris, France
5 INSERM, U 567, Paris, France

Vasodilatation is a vital mechanism of systemic blood flow regulation that occurs during periods of increased energy demand. The AMP-dependent protein kinase (AMPK) is a serine/threonine kinase that is activated by conditions that increase the AMP-to-ATP ratio, such as exercise and metabolic stress. We hypothesized that AMPK could trigger vasodilatation and participate in blood flow regulation. Rings of thoracic aorta were isolated from C57Bl6 mice and mice deficient in the AMPK catalytic {alpha}1 (AMPK{alpha}1–/–) or {alpha}2 (AMPK{alpha}2–/–) subunit and their littermate controls, and mounted in an organ bath. Aortas were preconstricted with phenylephrine (1 µM) and activation of AMPK was induced by addition of increasing concentrations of 5-aminoimidazole-4-carboxamide-1-beta-D-ribofuranoside (AICAR). AICAR (0.1–3 mM) dose-dependently induced relaxation of precontracted C57BL6, AMPK{alpha}1+/+ and {alpha}2+/+ aorta (P < 0.001, n = 5–7 per group). This AICAR induced vasorelaxation was not inhibited by the addition of adenosine receptor antagonists. Moreover, when aortic rings were freed of endothelium by gentle rubbing, AICAR still induced aortic ring relaxation, suggesting a direct effect of AICAR on smooth muscle cells. When aortic rings were pretreated with L-NMMA (30 µM) to inhibit nitric oxide synthase activity, AICAR still induced relaxation. Western blot analysis of C57Bl6 mice denuded aorta showed that AMPK was phosphorylated after incubation with AICAR and that AMPK{alpha}1 was the main catalytic subunit expressed. Finally, AICAR-induced relaxation of aortic rings was completely abolished in AMPK{alpha}1–/– but not AMPK{alpha}2–/– mice. Taken together, the results show that activation of AMPK{alpha}1 but not AMPK{alpha}2 is able to induce aortic relaxation in mice, in an endothelium- and eNOS-independent manner.

(Received 17 March 2007; accepted after revision 13 April 2007; first published online 19 April 2007)
Corresponding author F. Goirand : LPPCE Faculté de Médecine, 7, bd Jeanne d'Arc, BP 87900, 21079 Dijon Cedex, France. Email: goirand.francoise{at}wanadoo.fr






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