MicroRNA-10a is crucial for endothelial response to different flow patterns via interaction of retinoid acid receptors and histone deacetylases

Ding Yu Lee, Ting Er Lin, Chih I. Lee, Jing Zhou, Yi Hsuan Huang, Pei Ling Lee, Yu Tsung Shih, Shu Chien, Jeng Jiann Chiu

Research output: Contribution to journalArticlepeer-review

20 Citations (Scopus)

Abstract

Histone deacetylases (HDACs) and microRNAs (miRs) have emerged as two important epigenetic factors in the regulation of vascular physiology. This study aimed to elucidate the relationship between HDACs and miRs in the hemodynamic modulation of endothelial cell (EC) dysfunction. We found that miR-10a has the lowest expression among all examined shear-responsive miRs in ECs under oscillatory shear stress (OS), and a relatively high expression under pulsatile shear stress (PS). PS and OS alter EC miR-10a expression to regulate the expression of its direct target GATA6 and downstream vascular cell adhesion molecule (VCAM)-1. PS induces the expression, nuclear accumulation, and association of retinoid acid receptor-α (RARα) and retinoid X receptor-α (RXRα). RARα and RXRα serve as a "director" and an "enhancer," respectively, to enhance RARα binding to RA-responsive element (RARE) and hence miR-10a expression, thus down-regulating GATA6/VCAM-1 signaling in ECs. In contrast, OS induces associations of "repressors" HDAC-3/5/7 with RARα to inhibit the RARα-directed miR-10a signaling. The flow-mediated miR-10a expression is regulated by Krüppel-like factor 2 through modulation in RARα-RARE binding, with the consequent regulation in GATA6/VCAM-1 in ECs. These results are confirmed in vivo by en face staining on the aortic arch vs. the straight thoracic aorta of rats. Our findings identify a mechanism by which HDACs and RXRα modulate the hormone receptor RARα to switch miR-10a expression and hence the proinflammatory vs. anti-inflammatory responses of vascular endothelium under different hemodynamic forces.

Original languageEnglish
Pages (from-to)2072-2077
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume114
Issue number8
DOIs
Publication statusPublished - Feb 21 2017

Keywords

  • Endothelial cells
  • Histone deacetylase
  • Hormone receptor
  • microRNA
  • Shear stress

ASJC Scopus subject areas

  • General

Fingerprint Dive into the research topics of 'MicroRNA-10a is crucial for endothelial response to different flow patterns via interaction of retinoid acid receptors and histone deacetylases'. Together they form a unique fingerprint.

Cite this