Abstract
Smoking increases the risk of abdominal aortic aneurysm (AAA) in both humans and mice, although the underlying mechanisms are not completely understood. An adventitial aortic antigen, AAAP-40, has been partially sequenced. It has motifs with similarities to all three fibrinogen chains and appears to be connected in evolution to a large family of proteins called fibrinogen-related proteins. Fibrinogen may undergo non-enzymatic nitration, which may result from exposure to nitric oxide in cigarette smoke. Nitration of proteins renders them more immunogenic. It has recently been reported that anti-fibrinogen antibody promotes AAA development in mice. Also, anti-fibrinogen antibodies are present in patients with AAA. These matters are reviewed in the overall context of autoimmunity in AAA. The evidence suggests that smoking amplifies an auto-immune reaction that is critical to the pathogenesis of AAA.
Highlights
Compared with the relatively small effects of genetic mutations or polymorphisms on the risk for abdominal aortic aneurysm (AAA), smoking presents a much greater risk by as much as an order of magnitude
The evidence suggests that smoking amplifies an auto-immune reaction that is critical to the pathogenesis of AAA
A molecular explanation for the effect of smoking has been proposed [6]. The purpose of this communication is to explain the hypothesis that nitric oxide (NO) in tobacco smoke nitrates a protein related to the fibrinogen superfamily in the aortic adventitia and enhances its antigenicity
Summary
Compared with the relatively small effects of genetic mutations or polymorphisms on the risk for abdominal aortic aneurysm (AAA), smoking presents a much greater risk by as much as an order of magnitude. The risk-odds ratio of a well-established polymorphism associated with AAA, DAB2IP on chromosome 9q33.2, is 1.2 [1], and the risk-odds ratio for another polymorphism on 9p21 is 1.3 [2]. A molecular explanation for the effect of smoking has been proposed [6]. The purpose of this communication is to explain the hypothesis that nitric oxide (NO) in tobacco smoke nitrates a protein related to the fibrinogen superfamily in the aortic adventitia and enhances its antigenicity. I discuss four factors that are often associated with diseases of autoimmunity [7, 8]: genetic susceptibility, inflammation, matrix metalloproteinases (MMPs), and antibodies and autoantigens
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