Induction of microRNA-10a using retinoic acid receptor-α and retinoid x receptor-α agonists inhibits atherosclerotic lesion formation

Ding Yu Lee, Tung Lin Yang, Yi Hsuan Huang, Chih I. Lee, Li Jing Chen, Yu Tsung Shih, Shu Yi Wei, Wei Li Wang, Chih Cheng Wu, Jeng Jiann Chiu

Research output: Contribution to journalArticle

8 Citations (Scopus)

Abstract

Background and aims: MicroRNA (miR)-10a is a shear-regulated miR with the lowest expression in vascular endothelial cells (ECs) in athero-susceptible regions with oscillatory shear stress (OS). The aim of this study is to elucidate the relationship between EC miR-10a and atherosclerosis and develop a hemodynamics-based strategy for atherosclerosis treatment. Methods: A combination of in vitro flow system and in vivo experimental animals was used to examine the functional roles of EC miR-10a and its clinical applications in atherosclerosis. Results: En face staining showed that EC miR-10a is down-regulated in the inner curvature (OS region) of aortic arch in rats. Co-administration with retinoic acid receptor-α (RARα)- and retinoid X receptor-α (RXRα)-specific agonists rescued EC miR-10a expression in this OS region. These effects of OS and RARα/RXRα-specific agonists on EC miR-10a expression were confirmed by the in vitro flow system, and were modulated by the RARα-histone deacetylases complex, with the consequent modulation in the downstream GATA6/vascular cell adhesion molecule (VCAM)-1 signaling cascade. Animal studies showed that miR-10a levels are decreased in both aortic endothelium of atherosclerotic lesions and blood plasma from apolipoprotein E-deficient (ApoE−/−) mice. In vivo induction of EC miR-10a by administration of RARα/RXRα-specific agonists protects ApoE−/− mice from atherosclerosis through inhibition of GATA6/VCAM-1 signaling and inflammatory cell infiltration. Conclusions: Our findings indicate that down-regulation of miR-10a in aortic endothelium and blood serum is associated with atherosclerosis, and miR-10a has potential to be developed as diagnostic molecule for atherosclerosis. Moreover, EC miR-10a induction by RARα/RXRα-specific agonists is a potential hemodynamics-based strategy for atherosclerosis treatment.

Original languageEnglish
Pages (from-to)36-44
Number of pages9
JournalAtherosclerosis
Volume271
DOIs
Publication statusPublished - Apr 2018

Keywords

  • Atherosclerosis
  • Endothelial cell
  • MicroRNA
  • Retinoic acid receptor
  • Shear stress

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine

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