title: A new RXR agonist, HX630, suppresses intimal hyperplasia in a mouse blood flow cessation model.
abstract: 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.
authors.affiliation: Department of Cardiovascular Medicine, Tokyo, Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo 113-8519, Japan. goh.cvm@tmd.ac.jp
authors.forename: Go
authors.initials: G
authors.lastname: Haraguchi
authors.forename: Jun-Ichi
authors.initials: J
authors.lastname: Suzuki
authors.forename: Hisanori
authors.initials: H
authors.lastname: Kosuge
authors.forename: Masahito
authors.initials: M
authors.lastname: Ogawa
authors.forename: Noritaka
authors.initials: N
authors.lastname: Koga
authors.forename: Susumu
authors.initials: S
authors.lastname: Muto
authors.forename: Akiko
authors.initials: A
authors.lastname: Itai
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Kagechika
authors.forename: Koichi
authors.initials: K
authors.lastname: Shudo
authors.forename: Mitsuaki
authors.initials: M
authors.lastname: Isobe
mesh_terms: D000818:Animals; D001552:Benzazepines / Q000494:pharmacology*; D001565:Benzoates / Q000494:pharmacology*; D001783:Blood Flow Velocity; D002339:Carotid Arteries / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D015815:Cell Adhesion Molecules / Q000378:metabolism; D049109:Cell Proliferation; D002478:Cells, Cultured; D016207:Cytokines / Q000378:metabolism; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D042783:Endothelial Cells / Q000502:physiology; D006965:Hyperplasia / Q000503:physiopathology*; D053583:Interleukin-1beta / Q000494:pharmacology; D008297:Male; D051379:Mice; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000502:physiology*; D047488:Retinoid X Receptors / Q000819:agonists*; D017539:Tunica Intima / Q000378:metabolism / Q000473:pathology*
chemical_list: D001552:Benzazepines; D001565:Benzoates; D015815:Cell Adhesion Molecules; D016207:Cytokines; C422175:HX 630; D053583:Interleukin-1beta; D047488:Retinoid X Receptors