Understanding abdominal aortic aneurysm.

Abdominal aortic aneurysms occur in up to 9% of adults older than 65 years of age, and the rupture of these aneurysms accounts for about 15,000 deaths in the United States annually.1 Approximately 33,000 patients undergo repair of abdominal aortic aneurysms each year, with associated illness, death, and health care costs. Smoking is a major risk factor. Although aggressive management of hypertension and hyperlipidemia is recommended in patients with abdominal aortic aneurysms, therapies for these conditions have little effect on aneurysm growth and rupture. In this context, a recent study by Satoh and colleagues2 is welcome because it sheds new light on how abdominal aortic aneurysms form and thereby rekindles interest in a therapy that was shown to protect against experimental aneurysm formation more than a decade ago. Epidemiologic and pathological studies have yielded few clues to the cause of abdominal aortic aneurysms. Although abdominal aortic aneurysms frequently occur in patients with atherosclerosis and the two disease processes share several common risk factors, atherosclerotic lesions are predominantly intimal in location, whereas the media and adventitia are primarily involved in aneurysms. The hallmark pathologic feature of atherosclerosis is foam-cell formation, whereas aneurysms are typified by intense oxidative stress, inflammation, matrix degradation, and apoptosis of smooth-muscle cells.3 Inhibitors of matrix metalloproteinase are currently being tested in human aneurysmal disease, but their efficacy may be limited, in part because they are directed toward only one aspect of the disease process; thus, targeting factors that contribute to multiple aspects of the pathologic process of aneurysms would probably be of greater benefit. Studies in animal models have shown that angiotensin II induces vascular oxidative stress, inflammation, matrix degradation, and apoptosis of smooth-muscle cells and contributes experimentally to aneurysm formation.4 Studies in humans also suggest a role for angiotensin II in the pathogenesis of the disease. However, the cellular mechanisms that link these pathologic processes together to produce abdominal aortic aneurysms remain to be elucidated. Satoh et al. examined the role of cyclophilin A (encoded by peptidyl-prolyl isomerase A [Ppia]) in abdominal aortic aneurysms induced by the infusion of angiotensin II in mice with hyperlipidemia, an established model of aneurysm formation.4 Cyclophilin A, a member of the highly conserved and widely expressed family of proteins called the immunophilins, is the intracellular target of the immunosuppressive drug cyclosporine. Cyclosporine binds to cyclophilin A and forms a ternary complex with calcineurin, thereby inhibiting its activity. Inhibition of calcineurin blocks translocation of the nuclear factor of activated T cells to the nucleus, which in turn inhibits the transcription of inflammatory genes and T-cell activation. This inhibition forms the basis of the well-known immunomodulatory effects of cyclosporine. However, immunophilins also possess peptidyl-prolyl cis-trans-isomerase enzymatic activity. The peptidyl-prolyl cis-transisomerase domain of cyclophilin A facilitates binding to CD147, also known as an inducer of extracellular-matrix metalloproteinase. This binding causes CD147 to translocate to the cell surface, where it plays a critical role in stimulating matrix-metalloproteinase activity, leading to matrix degradation. This observation, coupled with reports that cyclophilin A is secreted by smoothmuscle cells in response to reactive oxygen species and triggers vascular inflammatory responses (Fig. 1), prompted the investigators to examine its role in the formation of abdominal aortic aneurysms. Deletion of Ppia in mice, which led to the absence of cyclophilin A in aortic tissues, prevented the formation of abdominal aortic aneurysms in response to infusion of angiotensin II. Aortic inflammation, oxidative stress, and matrix deg-