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

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

  • Proc Natl Acad Sci U S A. 2017 Feb 21;114(8):2072-2077. doi: 10.1073/pnas.1621425114.
Ding-Yu Lee 1,  Ting-Er Lin 1,  Chih-I Lee 1,  Jing Zhou 2,  Yi-Hsuan Huang 1,  Pei-Ling Lee 1,  Yu-Tsung Shih 1,  Shu Chien 3 4 5,  Jeng-Jiann Chiu 6 7 8
Affiliations

Affiliations

  • 1 Institute of Cellular and System Medicine, National Health Research Institutes, Miaoli 35053, Taiwan.
  • 2 Department of Physiology and Pathophysiology, Basic Medical College, Peking University, Beijing 100871, China.
  • 3 Department of Bioengineering, University of California, San Diego, La Jolla, CA 92093; [email protected] [email protected].
  • 4 Department of Medicine, University of California, San Diego, La Jolla, CA 92093.
  • 5 Institute of Engineering in Medicine, University of California, San Diego, La Jolla, CA 92093.
  • 6 Institute of Cellular and System Medicine, National Health Research Institutes, Miaoli 35053, Taiwan; [email protected] [email protected].
  • 7 Institute of Biomedical Engineering, National Tsing Hua University, Hsinchu 30013, Taiwan.
  • 8 College of Pharmacy, Taipei Medical University, Taipei 110, Taiwan.
PMID: 28167758 DOI: 10.1073/pnas.1621425114
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.

Keywords

endothelial cells; histone deacetylase; hormone receptor; microRNA; shear stress.

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