hx-630 and Hyperplasia

The nuclear receptor retinoid X receptor (RXR) forms heterodimers with other nuclear receptors and exerts anti-inflammatory effects. RXR is implicated in the progression of arteriosclerosis; however, the effects of selective RXR activation on smooth muscle cell (SMC) proliferation are unknown. We synthesized a novel RXR agonist, HX630, and examined its effect on vascular SMC (VSMC) proliferation. Male C57BL/6 mice (n=15) were subjected to ligation of the left carotid artery and fed 5 or 10 mg/kg/day HX630 for 4 weeks. HX630-fed mice showed significantly suppressed intimal hyperplasia progression compared to that in control mice (0.286+/-0.093 vs. 1.022+/-0.134 intima/media ratio, P<0.05). Immunohistochemistry of the carotid artery showed that HX630 suppressed cytokine and adhesion molecule staining in lesions undergoing intimal thickening. Interleukin (IL)-1beta-induced VSMC proliferation was inhibited by HX630 and the expression of IL-6 mRNA and protein in VSMCs was suppressed. The RXR agonist HX630 exerts antiproliferative effects in VSMCs in vivo and in vitro. Thus, the RXR may serve as a therapeutic target for vascular injury and intimal thickening.

Topics: Animals; Benzazepines; Benzoates; Blood Flow Velocity; Carotid Arteries; Cell Adhesion Molecules; Cell Proliferation; Cells, Cultured; Cytokines; Disease Models, Animal; Dose-Response Relationship, Drug; Endothelial Cells; Hyperplasia; Interleukin-1beta; Male; Mice; Muscle, Smooth, Vascular; Retinoid X Receptors; Tunica Intima