title: α1AMP-activated protein kinase preserves endothelial function during chronic angiotensin II treatment by limiting Nox2 upregulation.
abstract: OBJECTIVE
  Besides its well-described metabolic effects, vascular AMP-activated protein kinase (AMPK) can activate endothelial NO synthase, promotes angiogenesis, and limits endothelial cell apoptosis. The current study was designed to study the effects of α1AMPK deletion during vascular disease in vivo.
  
  
  RESULTS
  Chronic angiotensin II infusion at low subpressor doses caused a mild endothelial dysfunction that was significantly aggravated in α1AMPK-knockout mice. Unexpectedly, this endothelial dysfunction was not associated with decreased NO content, because NO levels measured by serum nitrite or electron paramagnetic resonance were even increased. However, because of parallel superoxide production, NO was consumed under production of peroxynitrite in angiotensin II-treated α1AMPK-knockout mice, associated with NADPH oxidase activation and Nox2 upregulation. As Nox2 is also a component of phagocyte NADPH oxidases, we found a vascular upregulation of several proinflammatory markers, including inducible NO synthase, vascular cell adhesion molecule-1, and cyclooxygenase-2. Cotreatment with the NADPH oxidase inhibitor apocynin was able to prevent vascular inflammation and also partially restored endothelial function in α1AMPK-knockout mice.
  
  
  CONCLUSIONS
  Our data indicate that in vivo α1AMPK deletion leads to Nox2 upregulation, resulting in endothelial dysfunction and vascular inflammation. This implicates basal AMPK activity as a protective, redox-regulating element in vascular homeostasis.
authors.affiliation: Department of Cardiology, II Medizinische Klinik und Poliklinik, Universitätsmedizin Mainz, Mainz, Germany.
authors.forename: Swenja
authors.initials: S
authors.lastname: Schuhmacher
authors.forename: Marc
authors.initials: M
authors.lastname: Foretz
authors.forename: Maike
authors.initials: M
authors.lastname: Knorr
authors.forename: Thomas
authors.initials: T
authors.lastname: Jansen
authors.forename: Marcus
authors.initials: M
authors.lastname: Hortmann
authors.forename: Philip
authors.initials: P
authors.lastname: Wenzel
authors.forename: Matthias
authors.initials: M
authors.lastname: Oelze
authors.forename: Andrei L
authors.initials: AL
authors.lastname: Kleschyov
authors.forename: Andreas
authors.initials: A
authors.lastname: Daiber
authors.forename: John F
authors.initials: JF
authors.lastname: Keaney
authors.forename: Gerhard
authors.initials: G
authors.lastname: Wegener
authors.forename: Karl
authors.initials: K
authors.lastname: Lackner
authors.forename: Thomas
authors.initials: T
authors.lastname: Münzel
authors.forename: Benoit
authors.initials: B
authors.lastname: Viollet
authors.forename: Eberhard
authors.initials: E
authors.lastname: Schulz
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D000804:Angiotensin II / Q000008:administration & dosage*; D000818:Animals; D051546:Cyclooxygenase 2 / Q000235:genetics / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004578:Electron Spin Resonance Spectroscopy; D004730:Endothelium, Vascular / Q000187:drug effects* / Q000201:enzymology / Q000503:physiopathology; D004789:Enzyme Activation; D004791:Enzyme Inhibitors / Q000494:pharmacology; D007249:Inflammation / Q000201:enzymology* / Q000235:genetics / Q000503:physiopathology / Q000517:prevention & control; D018836:Inflammation Mediators / Q000378:metabolism; D007263:Infusions, Parenteral; D008297:Male; D008562:Membrane Glycoproteins / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D000074662:NADPH Oxidase 2; D019255:NADPH Oxidases / Q000378:metabolism*; D009569:Nitric Oxide / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II / Q000235:genetics / Q000378:metabolism; D009573:Nitrites / Q000097:blood; D018384:Oxidative Stress / Q000187:drug effects; D030421:Peroxynitrous Acid / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D013481:Superoxides / Q000378:metabolism; D013997:Time Factors; D015854:Up-Regulation; D019010:Vascular Cell Adhesion Molecule-1 / Q000235:genetics / Q000378:metabolism; D014664:Vasodilation / Q000187:drug effects; D014665:Vasodilator Agents / Q000494:pharmacology
chemical_list: D004791:Enzyme Inhibitors; D018836:Inflammation Mediators; D008562:Membrane Glycoproteins; D009573:Nitrites; D012333:RNA, Messenger; D019010:Vascular Cell Adhesion Molecule-1; D014665:Vasodilator Agents; D013481:Superoxides; D000804:Angiotensin II; D030421:Peroxynitrous Acid; D009569:Nitric Oxide; D052247:Nitric Oxide Synthase Type II; C496317:Nos2 protein, mouse; C077623:Ptgs2 protein, mouse; D051546:Cyclooxygenase 2; C488842:Cybb protein, mouse; D000074662:NADPH Oxidase 2; D019255:NADPH Oxidases; C548179:Prkaa1 protein, mouse; D055372:AMP-Activated Protein Kinases