The link between tobacco use and aneurysms of the abdominal aorta is well established, but the specific mechanisms involved have remained elusive for decades. A new study indicates that nicotine is the major culprit in cigarette smoke and provides a common mechanism of aneurysm formation that may allow the development of drugs to treat this disease, for which currently only surgical treatments exist (pages 902–910).
Abdominal aortic aneurysm is an enlargement of the abdominal aorta that represents a difficult clinical problem because the initial symptom is often rupture of the aneurysm1, an event with a mortality exceeding 70% (ref. 2), despite advances in surgical treatment3. These aneurysms start as small dilatations of the abdominal aorta that gradually expand over the course of years with the risk of rupture increasing drastically once the aneurysm reaches a diameter of 5 cm or more. The only accepted treatment for these large aneurysms is surgical open or endovascular graft placement. Early detection of smaller abdominal aneurysms is important because it enables clinicians to observe aneurysm expansion and intervene before rupture. However, prophylactic surgery for aneurysms smaller than 5 cm has not proven useful, so the current practice is watchful waiting until intervention is possible, and most aneurysms slowly expand over years.
Epidemiologic data have clearly linked tobacco smoking to aneurysm formation and a faster rate of expansion1,4. Pathological examination of human abdominal aortic aneurysm tissue has shown that it is characterized by intense oxidative stress, inflammation and matrix degradation5,6, but the mechanistic relationship linking aneurysm formation to smoking has remained elusive.
In this issue of Nature Medicine, Wang et al.7 break this impasse and provide new insights into the link between tobacco smoking and abdominal aortic aneurysms (Fig. 1). Using mouse models, they found that nicotine, the main dependence-forming ingredient of tobacco, increases aneurysm formation by stimulating the α2 isoform of AMP-activated protein kinase (AMPKα2) in vascular smooth muscle cells (VSMCs). Activation of AMPKα2, in turn, resulted in phosphorylation of activator protein 2α, a transcription factor that drives the expression of and smooth muscle cell release of matrix metalloproteinase 2, a matrix-degrading protein that functions to weaken the artery wall, thus facilitating aneurysm formation8.
This convincing link between abdominal aortic aneurysm formation and nicotine has important implications for patients that are trying to stop smoking. A mainstay of therapy for smoking cessation is nicotine replacement, as this treatment reduces the inevitable withdrawal symptoms that occur upon discontinuation of smoking. However, the data of Wang et al.7 suggest that patients with pre-existing abdominal aneurysms who are attempting to stop smoking need particular attention, as nicotine replacement therapy has the potential to exacerbate abdominal aortic aneurysm.
As AMPKα2 is required for nicotine-induced abdominal aneurysm formation and expansion, it follows that inhibition of this kinase could represent a new treatment for the disease. This premise is strengthened by additional data from the study of Wang et al.7. First, they used another common model of abdominal aortic aneurysm formation in mice, angiotensin II infusion, and observed that aneurysm formation in this model was also dependent on AMPKα2. Moreover, human abdominal aortic aneurysm tissue samples showed increased activity of AMPKα2 compared with aortic tissues from people without abdominal aortic aneurysms. Collectively, these observations suggest that AMPKα2 inhibition may help to treat early-stage abdominal aortic aneurysms and prevent their expansion and rupture. This concept is a welcome addition to the field of vascular disease, as there are currently no effective drugs to treat abdominal aortic aneurysm. Even today, smoking cessation is the mainstay of clinical management of aneurysm.
However, designing therapeutic strategies to inhibit AMPKα2 could present challenges. Overall, the AMP-activated kinases have three subunits (α, β and γ) with distinct isoforms (α1, α2, β1, β2, γ1, γ2 and γ3) and broad tissue distributions. This family of enzymes is principally involved in cellular adaptation to changing energy status (that is, metabolic stress) but also is activated in a variety of other settings that the cell may interpret as injurious. Animals lacking both catalytic isoforms of AMPK (α1 and α2) are not viable, indicating that this enzyme family is crucial in developmentally important pathways. Similarly, activation of AMPK is the mechanism for the world's most widely used diabetes treatment drug, metformin9. Thus, it is conceivable that AMPK inhibition for the treatment of abdominal aortic aneurysm could worsen diabetes or have other unintended consequences. Conversely, the findings of Wang et al.7 suggest that patients with diabetes on metformin with known abdominal aortic aneurysms warrant close scrutiny for aneurysm dilatation.
A similar cautionary note also applies to therapeutic inhibition of activator protein 2α, the transcription factor Wang et al.7 implicated in the matrix metalloproteinase upregulation that is key in aneurysm formation and dilatation. Activator protein 2α has been shown to be important for mammalian tumorigenesis, differentiation and development, and mice lacking activator protein 2α are not viable10. Consequently, any therapies based on inhibiting activator protein 2α will need to be scrutinized for unanticipated side effects.
In the search for new therapies using animal models, one limitation is the extent to which the animal models recapitulate the human condition. The mouse models used by Wang et al.7 reproducibly generate abdominal aneurysms, but in the suprarenal aorta. In contrast, most human aneurysms are located below the renal arteries, suggesting that mice may imperfectly model the human condition. In addition, the human disease occurs in later stages of life compared to the equivalent in mice and is associated with atherosclerosis and thrombosis, conditions not prevalent in the mouse model. Thus, there are important distinctions between mouse aneurysm models and aortic aneurysms in humans, indicating there could be challenges in developing new therapies for human abdominal aortic aneurysm using mouse models.
Despite these concerns, the study by Wang et al.7 provides an important molecular link between nicotine and the promotion of abdominal aortic aneurysms. This finding adds to a recent study that uncovered another molecular target of nicotine, microRNA-21 (miR-21), that is strongly upregulated in the course of aneurysm formation11. The upregulation of miR-21 seems to be protective, as inhibiting its expression accelerates aneurysm expansion. Collectively, these two studies begin to identify molecular targets for nicotine that provide us with new potential therapeutic strategies for a disease that currently has no established medical therapy.
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The authors declare no competing financial interests.
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Sugamura, K., Keaney, J. Nicotine: linking smoking to abdominal aneurysms. Nat Med 18, 856–858 (2012). https://doi.org/10.1038/nm.2714
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