title: The hypotensive effect of acute and chronic AMP-activated protein kinase activation in normal and hyperlipidemic mice.
abstract: AMP-activated protein kinase (AMPK) is present in the arterial wall and is activated in response to cellular stressors that raise AMP relative to ADP/ATP. Activation of AMPK in vivo lowers blood pressure but the influence of hyperlipidemia on this response has not been studied. ApoE(-/-) mice on high fat diet for 6weeks and age-matched controls were treated with the AMPK activator, AICAR daily for two weeks. Under anesthesia, the carotid artery was cannulated for blood pressure measurements. Aortic tissue was removed for in vitro functional experiments and AMPK activity was measured in artery homogenates by Western blotting. ApoE(-/-) mice had significantly raised mean arterial pressure; chronic AICAR treatment normalized this but had no effect in normolipidemic mice, whereas acute administration of AICAR lowered mean arterial pressure in both groups. Chronic AICAR treatment increased phosphorylation of AMPK and its downstream target acetyl-CoA carboxylase in normolipidemic but not ApoE(-/-) mice. In aortic rings, AMPK activation induced vasodilation and an anticontractile effect, which was attenuated in ApoE(-/-) mice. This study demonstrates that hyperlipidemia dysregulates the AMPK pathway in the arterial wall but this effect can be reversed by AMPK activation, possibly through improving vessel compliance.
authors.affiliation: Institute of Cardiovascular and Medical Sciences, College of Medical, Veterinary & Life Sciences, University of Glasgow, Glasgow G12 8QQ, UK.
authors.forename: Fiona H
authors.initials: FH
authors.lastname: Greig
authors.affiliation: Institute of Cardiovascular and Medical Sciences, College of Medical, Veterinary & Life Sciences, University of Glasgow, Glasgow G12 8QQ, UK.
authors.forename: Marie-Ann
authors.initials: MA
authors.lastname: Ewart
authors.affiliation: Institute of Cardiovascular and Medical Sciences, College of Medical, Veterinary & Life Sciences, University of Glasgow, Glasgow G12 8QQ, UK.
authors.forename: Eilidh
authors.initials: E
authors.lastname: McNaughton
authors.affiliation: Institute of Cardiovascular and Medical Sciences, College of Medical, Veterinary & Life Sciences, University of Glasgow, Glasgow G12 8QQ, UK.
authors.forename: Josephine
authors.initials: J
authors.lastname: Cooney
authors.affiliation: School of Life & Health Sciences, Aston University, Birmingham B4 7ET, UK.
authors.forename: Corinne M
authors.initials: CM
authors.lastname: Spickett
authors.affiliation: Institute of Cardiovascular and Medical Sciences, College of Medical, Veterinary & Life Sciences, University of Glasgow, Glasgow G12 8QQ, UK. Electronic address: simon.kennedy@glasgow.ac.uk.
authors.forename: Simon
authors.initials: S
authors.lastname: Kennedy
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000378:metabolism*; D000103:Acetyl-CoA Carboxylase / Q000378:metabolism; D000620:Aminoimidazole Carboxamide / Q000031:analogs & derivatives / Q000378:metabolism; D000818:Animals; D000959:Antihypertensive Agents / Q000494:pharmacology*; D001011:Aorta / Q000187:drug effects / Q000378:metabolism; D001794:Blood Pressure / Q000187:drug effects; D004789:Enzyme Activation / Q000187:drug effects*; D006949:Hyperlipidemias / Q000188:drug therapy* / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D010766:Phosphorylation / Q000187:drug effects; D012265:Ribonucleotides / Q000378:metabolism; D014664:Vasodilation / Q000187:drug effects
chemical_list: D000959:Antihypertensive Agents; D012265:Ribonucleotides; D000620:Aminoimidazole Carboxamide; D055372:AMP-Activated Protein Kinases; D000103:Acetyl-CoA Carboxylase; C031143:AICA ribonucleotide
keywords: AICAR; AMPK; Hyperlipidemia; Hypotension; Mean arterial blood pressure