Retinoid X Receptor Agonists Impair Arterial Mononuclear Cell Recruitment through Peroxisome Proliferator-Activated Receptor-γ Activation

Mononuclear cell migration into the vascular subendothelium constitutes an early event of the atherogenic process. Because the effect of retinoid X receptor (RXR)alpha on arterial mononuclear leukocyte recruitment is poorly understood, this study investigated whether RXR agonists can affect this response and the underlying mechanisms involved. Decreased RXR alpha expression was detected after 4 h stimulation of human umbilical arterial endothelial cells with TNF-alpha. Interestingly, under physiological flow conditions, TNF-alpha-induced endothelial adhesion of human mononuclear cells was concentration-dependently inhibited by preincubation of the human umbilical arterial endothelial cells with RXR agonists such as bexarotene or 9-cis-retinoid acid. RXR agonists also prevented TNF-alpha-induced VCAM-1 and ICAM-1 expression, as well as endothelial growth-related oncogene-alpha and MCP-1 release. Suppression of RXR alpha expression with a small interfering RNA abrogated these responses. Furthermore, inhibition of MAPKs and NF-kappa B pathways were involved in these events. RXR agonist-induced antileukocyte adhesive effects seemed to be mediated via RXR alpha/peroxisome proliferator-activated receptor (PPAR)gamma interaction, since endothelial PPAR gamma silencing abolished their inhibitory responses. Furthermore, RXR agonists increased RXR/PPAR gamma interaction, and combinations of suboptimal concentrations of both nuclear receptor ligands inhibited TNF-alpha-induced mononuclear leukocyte arrest by 60-65%. In vivo, bexarotene dose-dependently inhibited TNF-alpha-induced leukocyte adhesion to the murine cremasteric arterioles and decreased VCAM-1 and ICAM-1 expression. Therefore, these results reveal that RXR agonists can inhibit the initial inflammatory response that precedes the atherogenic process by targeting different steps of the mononuclear recruitment cascade. Thus, RXR agonists may constitute a new therapeutic tool in the control of the inflammatory process associated with cardiovascular disease. The Journal of Immunology, 2012, 189: 411-424.