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A new RXR agonist, HX630, suppresses intimal hyperplasia in a mouse blood flow cessation model
Go Haraguchi1, Jun-Ichi Suzuki, Hisanori Kosuge
1Department of Cardiovascular Medicine, Tokyo, Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo 113-8519, Japan. goh.cvm@tmd.ac.jp
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.
Insights
A novel Retinoid X Receptor (RXR) agonist, HX630, significantly reduced vascular smooth muscle cell proliferation and intimal hyperplasia in mice. This suggests RXR activation is a potential therapeutic target for vascular injury.
Area of Science:
- Cardiovascular Biology
- Molecular Pharmacology
- Cell Biology
Background:
- Nuclear receptors, including Retinoid X Receptor (RXR), play roles in inflammation and arteriosclerosis.
- The specific impact of selective RXR activation on vascular smooth muscle cell (VSMC) proliferation remains largely unexplored.
- Arteriosclerosis involves abnormal VSMC proliferation and intimal hyperplasia.
Purpose of the Study:
- To investigate the effects of a novel RXR agonist, HX630, on vascular smooth muscle cell proliferation.
- To determine if selective RXR activation can mitigate intimal hyperplasia and associated inflammatory markers.
Main Methods:
- Synthesis of a novel RXR agonist, HX630.
- In vivo study using a mouse carotid artery ligation model with HX630 administration.
- In vitro assessment of HX630's effect on Interleukin-1beta-induced VSMC proliferation and IL-6 expression.
Main Results:
- HX630 administration significantly suppressed intimal hyperplasia progression in mice.
- Immunohistochemistry revealed reduced cytokine and adhesion molecule staining in HX630-treated arteries.
- HX630 inhibited Interleukin-1beta-induced VSMC proliferation and suppressed IL-6 mRNA and protein expression in vitro.
Conclusions:
- The RXR agonist HX630 demonstrates potent antiproliferative effects on vascular smooth muscle cells both in vivo and in vitro.
- Selective RXR activation via HX630 represents a promising therapeutic strategy for managing vascular injury and intimal thickening.
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