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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2004;24:1789.)
© 2004 American Heart Association, Inc.

Vascular Biology

Proinflammatory Cytokines Regulate LOX-1 Expression in Vascular Smooth Muscle Cells

Oliver Hofnagel; Birgit Luechtenborg; Katrin Stolle; Stefan Lorkowski; Heike Eschert; Gabriele Plenz; Horst Robenek

From the Institute for Arteriosclerosis Research (O.H., B.L., K.S., S.L., G.P., H.R.), University of Muenster, Germany; the Department of Cardiology and Angiology (G.P.), Hospital of the University of Muenster, Germany; and the Department of Thoracic and Cardiovascular Surgery (H.E., G.P.), Hospital of the University of Muenster, Germany.

Correspondence to Oliver Hofnagel, Institute for Arteriosclerosis Research, Domagkstr. 3, D-48149 Münster, Germany. E-mail hofnagel{at}uni-muenster.de

Objective— Atherogenesis represents a type of chronic inflammation and involves elements of the immune response, eg, the expression of proinflammatory cytokines. In advanced atherosclerotic lesions, lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1) is expressed in endothelial cells, macrophages, and smooth muscle cells (SMCs). In vitro, the expression of LOX-1 is induced by inflammatory cytokines like TNF- and transforming growth factor (TGF)-ß. Therefore, LOX-1 is thought to be upregulated locally in response to cytokines in vivo.

Methods and Results— We determined by reverse-transcription polymerase chain reaction (PCR) and Western blot analysis whether the mediators of the acute phase response in inflammation, IL-1, IL-1ß, and TNF-, regulate LOX-1 expression in cultured SMC, and whether this regulation is influenced by peroxisome proliferator-activated receptor (PPAR). We studied by immunohistochemistry whether these cytokines are spatially correlated with LOX-1 expression in advanced atherosclerotic lesions. We found upregulation of LOX-1 expression in SMC in a dose- and time-dependent manner after incubation with IL-1, IL-1ß, and TNF-. Simultaneous incubation with these cytokines at saturated concentrations had an additive effect on LOX-1 expression. The PPAR activator, 15d-PGJ₂, however, inhibited IL-1ß–induced upregulation of LOX-1. In the intima of atherosclerotic lesions regions of IL-1, IL-1ß, and TNF- expression corresponded to regions of LOX-1 expression.

Conclusion— We suppose that upregulated LOX-1 expression in SMC of advanced atherosclerotic lesions is a response to these proinflammatory cytokines. Moreover, the proinflammatory effects of these cytokines can be decreased by the antiinflammatory effect of PPAR.

The proinflammatory cytokines interleukin (IL)-1, IL-1ß, and tumor necrosis factor (TNF)- promote the expression of LOX-1 in cultured smooth muscle cells (SMC), and LOX-1 expression colocalizes with these cytokines in advanced atherosclerotic lesions. Therefore, LOX-1 expression in SMC may be upregulated locally by these cytokines during atherogenesis.

Key Words: atherosclerosis • LOX-1 • scavenger receptor • smooth muscle cell • interleukin

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