Aortic Aneurysm May Be Treatable with Asthma Drugs

A new study shows that asthma drugs that block cysteinyl-leukotrienes are a potential treatment for abdominal aortic aneurysms (AAAs) by reducing the breakdown of vessel wall tissue and the dilation of the aortic wall.

Researchers at the Karolinska Institutet (Stockholm, Sweden) found that messenger RNA (mRNA) levels for the three key enzymes in the biosynthesis of cysteinyl-leukotrienes--5-lipoxygenase (5-LO), 5-LO-activating protein (FLAP), and LTC4 synthase (LTC4S)--are significantly increased in the wall of human AAAs. In contrast, mRNA levels of LTA4 hydrolase (the enzyme responsible for the biosynthesis of LTB4) are not similarly increased. The researchers revealed that focal expression of 5-LO, FLAP, and LTC4S proteins in the media and adventitia--localized in areas rich in inflammatory cells--including macrophages, neutrophils, and mast cells. Thus, human AAA wall tissue converts arachidonic acid and the unstable epoxide LTA4 into significant amounts of cysteinyl-leukotrienes, and to a lesser extent LTB4.

According to the researchers, the increased expression of LTC4S, together with the predominant formation of cysteinyl-leukotrienes and effects on matrix metalloproteinase (MMP) 2 and 9 production, suggests a mechanism by which leukotrienes may promote matrix degradation in the AAA wall. The researchers also found that introduction of an asthma drug blocked the cysteinyl-leukotrienes, and thus impeded the release of the harmful MMPs. Their results suggest that this type of asthma drug could be used to reduce aortic dilation, and hence the danger of a ruptured AAA. The study was published in the December 7, 2010, issue of the Proceedings of the National Academy of Sciences (PNAS).

"Cysteinyl-leukotrienes can stimulate the release of protein-digesting enzymes called metalloproteases, which can contribute to the weakening of the aortic wall and the development of an aneurysm," explained lead author Prof. Jesper Haeggström, PhD, of the department of medical biochemistry and biophysics. "These asthma drugs are both efficacious and safe, and we should soon be able to test any positive effect they might have on aortic aneurysm."

Leukotrienes are arachidonic acid-derived lipid mediators involved in the pathogenesis and progression of diverse inflammatory disorders. The cysteinyl-leukotrienes LTC4, LTD4, and LTE4 are important mediators of asthma, and LTB4 has recently been implicated in atherosclerosis.

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