Editors' ChoiceVascular Disease

Another Smoking Gun

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Science Translational Medicine  25 Jul 2012:
Vol. 4, Issue 144, pp. 144ec133
DOI: 10.1126/scitranslmed.3004600

Although it’s no news that cigarette smoking is bad for your heart and blood vessels, the mechanisms by which smoking causes vascular disease remain an area of active and important study. In addition to thousands of other toxic chemicals, cigarette smoke is loaded with free radicals and particulate matter, which for decades have been thought to be the primary culprits in causing cardiovascular disease. A new study by Wang and colleagues not only provides definitive evidence of a causal link between smoking and abdominal aortic aneurysm (AAA), which until now had been associated only in observational studies, but also identifies nicotine as a major cause of AAA, at least in an animal model.

AAA is a focal weakening and dilatation of the wall of the abdominal aorta that frequently goes undetected until it results in catastrophic rupture, with a very high associated mortality. Using mouse models of this condition, Wang et al. demonstrated that nicotine infusion alone can markedly increase the incidence of AAA without inducing significant changes in heart rate or blood pressure. Next, the authors systematically used a combination of in vivo studies in knockout mice and in vitro studies of vascular smooth muscle cells in order to identify the specific serine/threonine protein kinase (AMPK-α2) that mediates the nicotine-AAA association and clarify the mechanism that leads to the aortic wall damage. To bring this work back into the clinical realm, the authors then measured AMPK-α2 activity in aortic tissue from autopsy specimens of patients who did or did not have AAA and in the blood of living smokers and nonsmokers; AMPK-α2 activity was higher in the AAA autopsy specimens and in blood from smokers relative to controls (non-AAA autopsy specimens and blood from nonsmokers).

The methodical and thorough study by Wang et al. implies that nicotine itself is a major driver of the pathogenesis of AAA in humans. These findings have important ramifications for clinical care, because smokers who are attempting to quit or are hospitalized for medical or surgical treatment are often treated with nicotine-replacement therapy. In addition, these findings have important implications for our understanding of the pathogenesis of other tobacco-related diseases, in which nicotine’s worst effects are often thought to be its addictive properties. Although other components of tobacco smoke are clearly major contributors to the development of cardiovascular and pulmonary disease, the role of nicotine (and potentially nicotine replacement) in driving these diseases warrants further study.

S. Wang et al., 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]

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