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Metabolic activation of AMP kinase in vascular smooth muscle

Departments of ¹Biomedical Sciences and ²Medical Pharmacology and Physiology, ³Dalton Cardiovascular Research Center, and Centers for ⁴Diabetes and Cardiovascular Health and ⁵Gender Physiology and Environmental Adaptations, University of Missouri, Columbia, Missouri

Submitted 22 January 2004 ; accepted in final form 10 September 2004

AMP-activated kinase (AMPK) is a highly conserved heterotrimeric kinase that functions as a metabolic master switch to coordinate cellular enzymes involved in carbohydrate and fat metabolism that regulate ATP conservation and synthesis. AMPK is activated by conditions that increase AMP-to-ATP ratio, such as exercise and metabolic stress. In the present study, we probed whether AMPK was expressed in vascular smooth muscle and would be activated by metabolic stress. Endothelium-denuded porcine carotid artery segments were metabolically challenged with 2-deoxyglucose (10 mM) plus N₂ (N₂-2DG). These vessels exhibited a rapid increase in AMPK activity by 1 min that was near maximal by 20 min. AMPK inactivation on return to normal physiological saline was 50% in 1 min and fully recovered by 5 min. Immunoprecipitation of the ₁- and ₂-catalytic subunit followed by immunoblot analysis for [P]Thr¹⁷²-AMPK indicates that ₁-AMPK accounts for all activity. Little if any ₂-AMPK was detected in carotid smooth muscle. AMPK activity was not increased by contractile agonist (endothelin-1) or by the reported AMPK activators 5-aminoimidazole-4-carboxamide ribofuranoside (2 mM), metformin (2 mM), or phenformin (0.2 mM). AMPK activation by N₂-2DG was associated with a rapid and pronounced reduction in endothelin-induced force and reduced phosphorylation of Akt and Erk 1/2. These data demonstrate that AMPK expression differs in vascular smooth muscle compared with striated muscles and that activation and inactivation after metabolic stress occur rapidly and are associated with signaling pathways that may regulate smooth-muscle contraction

porcine; carotid artery; 2-deoxyglucose; smooth muscle; adenosine 5'-monophosphate protein kinase

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