Fn14 Is Upregulated in Cytokine-Stimulated Vascular Smooth Muscle Cells and Is Expressed in Human Carotid Atherosclerotic Plaques

Abstract

Interaction between different members of the tumor necrosis factor superfamily and their receptors elicits diverse biologic actions that are implicated in the pathogenesis of atherosclerosis. We have analyzed the expression of Fn14 and its ligand TWEAK in carotid atherosclerotic plaques and its potential modulation by atorvastatin in vivo. Furthermore, we have studied whether proinflammatory cytokines regulate Fn14 expression in human aortic smooth muscle cells (hASMCs) in culture as well as the potential regulation by atorvastatin treatment. Fn14 and TWEAK expression was analyzed in human carotid atherosclerotic plaques. Furthermore, Fn14 expression was studied in hASMCs in culture. Fn14 and TWEAK are expressed in macrophages and smooth muscle cells in carotid atherosclerotic plaques. Proinflammatory cytokines (interleukin-1beta and interferon-gamma) upregulate Fn14 expression in hASMCs. This effect was prevented by atorvastatin treatment and reversed by mevalonate and geranylgeranyl pyrophosphate. Geranylgeranyl transferase inhibitor, toxin B (Rac and Rho inhibitor), C3 exoenzyme (Rho inhibitor), and Y-27632 (Rho kinase inhibitor) also decreased Fn14 expression, implicating the Rho/Rho kinase pathway in the regulation of Fn14 expression. Finally, atorvastatin treatment reduced Fn14 expression in vivo. TWEAK and Fn14 are expressed in atherosclerotic plaques and could be novel mediators of atherosclerosis. Atorvastatin diminishes Fn14 expression in vitro and in vivo providing novel information of the beneficial properties of statins.