Smoking is a primary risk factor for abdominal aortic aneurysm (AAA). Wang et al. found that nicotine induced AAA in mice, as did angiotensin II (AngII) infusion, a known mouse model for AAA. Deletion of the gene encoding adenosine monophosphate (AMP)–regulated protein kinase (AMPK)–α2, but not the one encoding AMPK-α1, reduced the incidence of AAA in mice treated with nicotine or AngII. Matrix metallopeptidase 2 (MM2), which contributes to AAA formation, had higher activity, mRNA abundance, and protein concentration in isolated aortas of mice treated with nicotine or AngII, and these increases in activity and abundance were abrogated in mice in which the gene encoding AMPK-α2 was knocked out. Human vascular smooth muscle cells (VSMCs) treated with nicotine or AngII had increased AMPK-α2 activity and phosphorylation at Thr172, as well as increased activity and abundance of MM2 mRNA and protein. Inhibition of AMPK-α2 by small interfering RNA (siRNA) or Compound C abrogated the effects of nicotine or AngII on MM2 in human VSMCs. Knockdown of AP-2α, a transcription factor required for MM2 expression, prevented the nicotine- or AngII-induced increase in MM2 abundance and activity in human VSMCs. AMPK-α2, but not AMPK-α1, was present in the nucleus of the VSMCs along with AP-2α. Immunoprecipitation studies both with lysates and with purified proteins showed that AMPK-α2 and AP-2α interact. AP-2α was phosphorylated in cells that were stimulated with nicotine or AngII. AMPK-α2 phosphorylated AP-2α in vitro at Ser219. In human VSMCs, expression of AP-2α with an S219A mutation abrogated the nicotine- or AngII-induced increase in MM2 activity and abundance. Thus, nicotine or AngII appears to stimulate AMPK-α2 activation and translocation to the nucleus, where it binds to and phosphorylates AP-2α, leading to aberrant expression of MM2 and consequent degradation of the extracellular matrix, which contributes to AAA. Inhibition of these molecular targets may lead to promising therapeutics (see commentary by Sugamura and Keaney).
S. Wang, C. Zhang, M. Zhang, B. Liang, H. Zhu, J. Lee, B. Viollet, L. Xia, Y. Zhang, M.-H. Zou, Activation of AMP-activated protein kinase α2 by nicotine instigates formation of abdominal aortic aneurysms in mice in vivo. Nat. Med. 18, 902–910 (2012). [PubMed]
K. Sugamura, J. F. Keaney, Jr., Nicotine: Linking smoking to abdominal aneurysms. Nat. Med. 18, 856–858 (2012). [PubMed]