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

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-α and transforming growth factor (TGF)-β. 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-1α, IL-1β, and TNF-α, regulate LOX-1 expression in cultured SMC, and whether this regulation is influenced by peroxisome proliferator-activated receptor γ (PPARγ). 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-1α, IL-1β, and TNF-α. Simultaneous incubation with these cytokines at saturated concentrations had an additive effect on LOX-1 expression. The PPARγ activator, 15d-PGJ2, however, inhibited IL-1β–induced upregulation of LOX-1. In the intima of atherosclerotic lesions regions of IL-1α, IL-1β, and TNF-α 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 PPARγ.