title: Activation of AMP-activated protein kinase α2 by nicotine instigates formation of abdominal aortic aneurysms in mice in vivo.
abstract: Smoking is the only modifiable risk factor that is associated with the development, expansion and rupture of abdominal aortic aneurysm (AAA). However, the causative link between cigarette smoke and AAA is unknown. Here we report a causative link between smoking and AAA in vivo. Acute infusion of angiotensin II (AngII) or nicotine, a major component of cigarette smoke, markedly increased the incidence of AAA in apolipoprotein E (apoE) knockout (Apoe(-/-)) mice and in mice deficient in both apoE and the AMP-activated kinase α1 subunit (AMPK-α1) (Apoe(-/-); Prkaa1(-/-) mice). In contrast, genetic deletion of AMPK-α2 (Apoe(-/-); Prkaa2(-/-) mice) ablated nicotine- or AngII-triggered AAA in vivo. Mechanistically, we found that both nicotine and AngII activated AMPK-α2 in cultured vascular smooth muscle cells (VSMCs), resulting in the phosphorylation of activator protein 2α (AP-2α) and consequent matrix metallopeptidase 2 (MMP2) gene expression. We conclude that smoking (through nicotine) instigates AAA through AMPK-α2–mediated AP-2α–dependent MMP2 expression in VSMCs.
authors.affiliation: Department of Medicine, Division of Molecular Medicine, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, USA.
authors.forename: Shuangxi
authors.initials: S
authors.lastname: Wang
authors.forename: Cheng
authors.initials: C
authors.lastname: Zhang
authors.forename: Miao
authors.initials: M
authors.lastname: Zhang
authors.forename: Bin
authors.initials: B
authors.lastname: Liang
authors.forename: Huaiping
authors.initials: H
authors.lastname: Zhu
authors.forename: Jiyeon
authors.initials: J
authors.lastname: Lee
authors.forename: Benoit
authors.initials: B
authors.lastname: Viollet
authors.forename: Lijun
authors.initials: L
authors.lastname: Xia
authors.forename: Yun
authors.initials: Y
authors.lastname: Zhang
authors.forename: Ming-Hui
authors.initials: MH
authors.lastname: Zou
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000502:physiology*; D000804:Angiotensin II / Q000494:pharmacology; D000818:Animals; D017544:Aortic Aneurysm, Abdominal / Q000139:chemically induced*; D002478:Cells, Cultured; D006801:Humans; D020778:Matrix Metalloproteinase 2 / Q000032:analysis; D051379:Mice; D008810:Mice, Inbred C57BL; D009131:Muscle, Smooth, Vascular / Q000201:enzymology; D009538:Nicotine / Q000633:toxicity*; D010766:Phosphorylation; D017382:Reactive Oxygen Species / Q000378:metabolism; D012907:Smoking / Q000009:adverse effects / Q000378:metabolism; D050656:Transcription Factor AP-2 / Q000502:physiology
chemical_list: D017382:Reactive Oxygen Species; D050656:Transcription Factor AP-2; D000804:Angiotensin II; D009538:Nicotine; C534978:Prkaa2 protein, mouse; D055372:AMP-Activated Protein Kinases; D020778:Matrix Metalloproteinase 2