Journal Article

Activation of AMP-activated protein kinase α2 by nicotine instigates formation of abdominal aortic aneurysms in mice in vivo

Zhang, Miao, Zou, Ming-Hui, Wang, Shuangxi, Zhang, Cheng, Lee, Jiyeon, Viollet, Benoit, Liang, Bin, Zhu, Huaiping, Xia, Lijun, Zhang, Yun

2012

Overview

Cigarette smoking raises the risk for cardiovascular disease, including the risk for abdominal aortic aneurysm. Shuangxi Wang et al . now show that nicotine itself is a causal factor in promoting abdominal aortic aneurysms in mice and delineate a pathogenic mechanism by which nicotine exposure leads to activation of the enzyme AMP-kinase in vascular smooth muscle cells and increased expression of the metallopeptidase MMP2. 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.

• Publisher: Nature Publishing Group US
• Subject: 692/420 / 692/699/75/593/1301 / AMP-Activated Protein Kinases - physiology / Angiotensin II - pharmacology / Animals / Aortic Aneurysm, Abdominal - chemically induced / Biomedical and Life Sciences / Biomedicine / Cancer Research / Cells, Cultured / Humans / Infectious Diseases / Matrix Metalloproteinase 2 - analysis / Metabolic Diseases / Mice / Mice, Inbred C57BL / Molecular Medicine / Muscle, Smooth, Vascular - enzymology / Neurosciences / Nicotine - toxicity / Phosphorylation / Reactive Oxygen Species - metabolism / Smoking - adverse effects / Smoking - metabolism / Transcription Factor AP-2 - physiology