Editorial Atherosclerosis Should We Stop TWEAKing It ?

Atherosclerosis is a very complex pathology. Over the past two decades we have come to appreciate that a major component of this pathological process is chronic inflammation. This inflammatory state is not only characterized by infiltration of lipid laden macrophages, the hallmark cell of this disease, into the vascular wall, but also is characterized by the infiltration of a host of other inflammatory cells. The complex interaction of inflammatory cells with the normal residents of the vascular wall (ie, endothelial and smooth muscle cells) directs the progression of the disease. Inflammatory cells secrete a variety of chemokines and cytokines which have a profound effect on the development and progression of the plaque. Moreover, many of these cytokines can mediate both proand antiatherogenic processes depending on the cellular milieu. The tumor necrosis factor (TNF) and TNF receptor (TNFR) superfamilies encompass numerous cytokines and receptors suggested to play a pivotal role in atherogenesis. Although many members of these families such as TNFand CD40 ligand and their putative receptors are considered to be proatherogenic,1–4 studies have also demonstrated an antiatherogenic role for others, including the p55 TNFR.5 TNF-like weak inducer of apoptosis (TWEAK) and its putative receptor, fibroblast growth factor-inducible 14 (Fn14), are also members of the TNF and TNFR superfamilies, respectively. Both TWEAK and Fn14 have been detected in human atherosclerotic plaques, suggesting that these molecules may also play a role in the atherogenic process. Clinical data are controversial with studies demonstrating either a positive or negative correlation with an increased risk for cardiovascular events.6 Although many studies have examined the role of TWEAK and Fn14 in renal pathologies, to date there have been few mechanistic studies addressing their role in atherosclerosis. However, a recent study examined the their role in cardiac function demonstrating that adenoviral over expression of TWEAK resulted in a dilated cardiomyopathy and cardiac dysfunction which was mediated by Fn14.7