5-lipoxygenase (5-LO) — an enzyme that is crucial for the synthesis of a class of pro-inflammatory lipids known as leukotrienes — has been identified as a potential therapeutic target for preventing life-threatening arterial ruptures that are often linked with atherosclerosis. Reporting in Nature Medicine, Funk and colleagues provide several lines of converging evidence that the 5-LO cascade is involved in the expression of inflammatory proteins in cells associated with atherosclerosis and contributes to the pathogenesis of aortic aneurysms.

An aneurysm is an abnormal enlargement or bulging of an artery that results from a weakening of the media, the smooth-muscle-cell-rich middle layer of the artery wall. The consequences of an aneurysm bursting can be extremely serious, and so surgery is typically used as a prophylactic measure once the aneurysm reaches a certain size; however, surgery is not without risk itself.

Several previous studies raised the possibility that 5-LO might have a role in cardiovascular disease, and so Funk and colleagues investigated the involvement of the 5-LO pathway in the formation of aneurysms induced by an atherogenic diet in mice that were rendered susceptible to atherosclerosis by knocking out the gene that encodes apolipoprotein E (APOE). Macrophages that expressed 5-LO were abundant in the adventitia (the outermost layer of the arterial wall) of these mice, which showed a high incidence of aneurysms in the aorta. However, mice in which the genes that encode both APOE and 5-LO were knocked out showed a much lower incidence and extent of aortic aneurysm development in the absence of changes in the degree of atherosclerosis. Furthermore, the activity of the metalloprotease MMP2, which is thought to be required for the remodelling involved in aneurysm formation, was significantly reduced in these mice compared with Apoe knockout mice.

A more detailed investigation of the 5-LO cascade using mouse and human cells revealed that the leukotriene LTD4 activates the expression of chemokines, including the macrophage inflammatory proteins MIP1-α in macrophages and MIP2 in endothelial cells, indicating a mechanism by which the 5-LO pathway might promote inflammation and aneurysm formation.

Taken together, these findings indicate that expression of 5-LO in adventitial macrophages generates leukotrienes, which in turn leads to the release of inflammatory cytokines, and, through indirect mechanisms, protease activity. The existence of these 5-LO-dependent inflammatory circuits highlights the possibility of using drugs that directly block their progression in patients who are susceptible to developing aneurysms as a promising alternative to surgical intervention.