Sulindac-derived retinoid X receptor-? modulator attenuates atherosclerotic plaque progression and destabilization in ApoE-/- mice.

ABSTRACT: BACKGROUND AND PURPOSE:Atherosclerosis is a chronic inflammatory disease, and retinoid X receptor-? (RXR?) is an intriguing anti-atherosclerosis target. This study investigated whether and how an RXR? 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-?B subunit were markedly reduced after K-80003 treatment. Also, K-80003 treatment inhibited 7-KC-induced p65 nuclear translocation, I?B? degradation, and transcription of NF-?B target genes. In addition, K-80003 inhibited NF-?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? was associated with decreased autophagic flux. Increasing cytoplasmic RXR? expression by overexpression of RXR?/385 mutant decreased autophagic flux in RAW264.7 cells. Finally, K-80003 strongly inhibited 7-KC-induced RXR? 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-?B proinflammatory pathway. Thus, targeting RXR?-mediated autophagy-inflammation axis by its noncanonical modulator may represent a promising strategy to treat atherosclerosis.

SUBMITTER: Shen L 

PROVIDER: S-EPMC6592870 | biostudies-literature | 2019 Jul

REPOSITORIES: biostudies-literature