Sulindac-derived retinoid X receptor-alpha modulator attenuates atherosclerotic plaque progression and destabilization in ApoE(-/-) mice
Shen, Linghong1; Sun, Zhe2; Nie, Peng3; Yuan, Ruosen3; Cai, Zhaohua3; Wu, Caizhe3; Hu, Liuhua3; Jin, Shuxuan3; Zhou, Hu4; Zhang, Xiaokun4,5; He, Ben1
2019-07
Source PublicationBRITISH JOURNAL OF PHARMACOLOGY
ISSN0007-1188
Volume176Issue:14Pages:2559-2572
Status已发表
DOI10.1111/bph.14682
AbstractBackground 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.
Indexed BySCI
Language英语
Funding ProjectNatural Science Foundation of Shanghai[15ZR1425800]
WOS Research AreaPharmacology & Pharmacy
WOS SubjectPharmacology & Pharmacy
WOS IDWOS:000472784200016
PublisherWILEY
WOS KeywordNF-KAPPA-B ; CONCISE GUIDE ; RXR-ALPHA ; IKK-BETA ; AUTOPHAGY ; INFLAMMATION ; DESIGN ; P62 ; INHIBITION ; BINDING
Original Document TypeArticle
Citation statistics
Cited Times:2[WOS]   [WOS Record]     [Related Records in WOS]
Document Type期刊论文
Identifierhttp://kms.shanghaitech.edu.cn/handle/2MSLDSTB/61121
Collection生命科学与技术学院_PI研究组_刘冀珑组
Corresponding AuthorZhang, Xiaokun; He, Ben
Affiliation1.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
Recommended Citation
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.
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