Sulindac-derived retinoid X receptor-alpha modulator attenuates atherosclerotic plaque progression and destabilization in ApoE(-/-) mice

doi:10.1111/bph.14682

	Sulindac-derived retinoid X receptor-alpha modulator attenuates atherosclerotic plaque progression and destabilization in ApoE(-/-) mice
	Shen, Linghong 1; Sun, Zhe2 ; Nie, Peng 3; Yuan, Ruosen 3; Cai, Zhaohua 3; Wu, Caizhe 3; Hu, Liuhua 3; Jin, Shuxuan 3; Zhou, Hu 4; Zhang, Xiaokun 4,5; He, Ben 1
	2019-07
发表期刊	BRITISH JOURNAL OF PHARMACOLOGY
ISSN	0007-1188
卷号	176 期号:14 页码:2559-2572
发表状态	已发表
DOI	10.1111/bph.14682
摘要	Background and Purpose Atherosclerosis is a chronic inflammatory disease, and retinoid X receptor-alpha (RXR alpha) is an intriguing anti-atherosclerosis target. This study investigated whether and how an RXR alpha modulator, K-80003, derived from a non-steroidal anti-inflammatory drug attenuates atherosclerotic plaque progression and destabilization. Experimental Approach Our previously established ApoE(-/-) mouse model of carotid vulnerable plaque progression was treated with K-80003 or vehicle for 4 or 8 weeks. Samples of carotid arteries and serum were collected to determine atherosclerotic lesion size, histological features, expression of related proteins, and lipid profiles. In vitro studies were carried out in 7-ketocholesterol (7-KC)-stimulated macrophages treated with or without K-80003. Key Results K-80003 significantly reduced lesion size, plaque rupture, macrophage infiltration, and inflammatory cytokine levels. Plaque macrophages positive for nuclear p65 (RelA) NF-kappa B subunit were markedly reduced after K-80003 treatment. Also, K-80003 treatment inhibited 7-KC-induced p65 nuclear translocation, I kappa B alpha degradation, and transcription of NF-kappa B target genes. In addition, K-80003 inhibited NF-kappa B pathway mainly through the reduction of p62/sequestosome 1 (SQSTM1), probably due to promotion of autophagic flux by K-80003. Mechanistically, cytoplasmic localization of RXR alpha was associated with decreased autophagic flux. Increasing cytoplasmic RXR alpha expression by overexpression of RXR alpha/385 mutant decreased autophagic flux in RAW264.7 cells. Finally, K-80003 strongly inhibited 7-KC-induced RXR alpha cytoplasmic translocation. Conclusions and Implications K-80003 suppressed atherosclerotic plaque progression and destabilization by promoting macrophage autophagic flux and consequently inhibited the p62/SQSTM1-mediated NF-kappa B proinflammatory pathway. Thus, targeting RXR alpha-mediated autophagy-inflammation axis by its noncanonical modulator may represent a promising strategy to treat atherosclerosis.
收录类别	SCI ; SCIE
语种	英语
资助项目	Natural Science Foundation of Shanghai[15ZR1425800]
WOS研究方向	Pharmacology & Pharmacy
WOS类目	Pharmacology & Pharmacy
WOS记录号	WOS:000472784200016
出版者	WILEY
WOS关键词	NF-KAPPA-B ; CONCISE GUIDE ; RXR-ALPHA ; IKK-BETA ; AUTOPHAGY ; INFLAMMATION ; DESIGN ; P62 ; INHIBITION ; BINDING
原始文献类型	Article
引用统计
文献类型	期刊论文
条目标识符	https://kms.shanghaitech.edu.cn/handle/2MSLDSTB/61121
专题	生命科学与技术学院_PI研究组_刘冀珑组
通讯作者	Zhang, Xiaokun; He, Ben
作者单位	1.Shanghai Jiao Tong Univ, Shanghai Chest Hosp, Dept Cardiol, 241 West Huaihai Rd, Shanghai 200030, Peoples R China 2.ShanghaiTech Univ, Sch Life Sci & Technol, Shanghai, Peoples R China 3.Shanghai Jiao Tong Univ, Renji Hosp, Sch Med, Dept Cardiol, Shanghai, Peoples R China 4.Xiamen Univ, Sch Pharmaceut Sci, Xiamen, Fujian, Peoples R China 5.Sandford Burnham Prebys Med Discovery Inst, Canc Ctr, 10901 N Torrey Pines Rd, La Jolla, CA 92037 USA
推荐引用方式 GB/T 7714	Shen, Linghong,Sun, Zhe,Nie, Peng,et al. Sulindac-derived retinoid X receptor-alpha modulator attenuates atherosclerotic plaque progression and destabilization in ApoE(-/-) mice[J]. BRITISH JOURNAL OF PHARMACOLOGY,2019,176(14):2559-2572.
APA	Shen, Linghong.,Sun, Zhe.,Nie, Peng.,Yuan, Ruosen.,Cai, Zhaohua.,...&He, Ben.(2019).Sulindac-derived retinoid X receptor-alpha modulator attenuates atherosclerotic plaque progression and destabilization in ApoE(-/-) mice.BRITISH JOURNAL OF PHARMACOLOGY,176(14),2559-2572.
MLA	Shen, Linghong,et al."Sulindac-derived retinoid X receptor-alpha modulator attenuates atherosclerotic plaque progression and destabilization in ApoE(-/-) mice".BRITISH JOURNAL OF PHARMACOLOGY 176.14(2019):2559-2572.