Published Online
on June 29, 2006

A more recent version of this article appeared on August 1, 2006

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Submitted on March 22, 2006
Accepted on May 16, 2006

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

Begoña Muñoz-García BsC; Jose Luis Martín-Ventura PhD; Elena Martínez MD; Santiago Sánchez MD; Gonzalo Hernández MD; Luis Ortega MD; Alberto Ortiz MD; Jesús Egido MD; and Luis Miguel Blanco-Colio PhD^*

From the Vascular Research Laboratory, Fundación Jiménez Díaz, Autonoma University, Madrid, Spain (B.M.-G., J.L.M.-V., A.O., J.E., L.M.B.-C.); R&D Department (E.M.), Medical Unit, Pfizer, Madrid, Spain (S.S., G.H.); and the Department of Pathology, Hospital Clínico San Carlos, Complutense University, Madrid, Spain (L.O.).

^* To whom correspondence should be addressed. E-mail: lblanco{at}fjd.es.

Background and Purpose--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.

Methods--Fn14 and TWEAK expression was analyzed in human carotid atherosclerotic plaques. Furthermore, Fn14 expression was studied in hASMCs in culture.

Results--Fn14 and TWEAK are expressed in macrophages and smooth muscle cells in carotid atherosclerotic plaques. Proinflammatory cytokines (interleukin-1 and interferon-) 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.

Conclusions--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.

Key words: carotid arteries • HMG-CoA reductase inhibitors • inflammation • Rho GTP-binding proteins • smooth muscle cells

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