A new RXR agonist, HX630, suppresses intimal hyperplasia in a mouse blood flow cessation model.
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.
Haraguchi
Go
G
Department of Cardiovascular Medicine, Tokyo, Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo 113-8519, Japan. goh.cvm@tmd.ac.jp
Suzuki
Jun-Ichi
J
Kosuge
Hisanori
H
Ogawa
Masahito
M
Koga
Noritaka
N
Muto
Susumu
S
Itai
Akiko
A
Kagechika
Hiroyuki
H
Shudo
Koichi
K
Isobe
Mitsuaki
M
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*
D001552:Benzazepines; D001565:Benzoates; D015815:Cell Adhesion Molecules; D016207:Cytokines; C422175:HX 630; D053583:Interleukin-1beta; D047488:Retinoid X Receptors