MicroRNA-10a is crucial for endothelial response to different flow patterns via interaction of retinoid acid receptors and histone deacetylases.
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.
Institute of Cellular and System Medicine, National Health Research Institutes, Miaoli 35053, Taiwan.
Ding-Yu
DY
Lee
Institute of Cellular and System Medicine, National Health Research Institutes, Miaoli 35053, Taiwan.
Ting-Er
TE
Lin
Institute of Cellular and System Medicine, National Health Research Institutes, Miaoli 35053, Taiwan.
Chih-I
CI
Lee
Department of Physiology and Pathophysiology, Basic Medical College, Peking University, Beijing 100871, China.
Jing
J
Zhou
Institute of Cellular and System Medicine, National Health Research Institutes, Miaoli 35053, Taiwan.
Yi-Hsuan
YH
Huang
Institute of Cellular and System Medicine, National Health Research Institutes, Miaoli 35053, Taiwan.
Pei-Ling
PL
Lee
Institute of Cellular and System Medicine, National Health Research Institutes, Miaoli 35053, Taiwan.
Yu-Tsung
YT
Shih
Department of Bioengineering, University of California, San Diego, La Jolla, CA 92093; shuchien@ucsd.edu jjchiu@nhri.org.tw.|Department of Medicine, University of California, San Diego, La Jolla, CA 92093.|Institute of Engineering in Medicine, University of California, San Diego, La Jolla, CA 92093.
Shu
S
Chien
Institute of Cellular and System Medicine, National Health Research Institutes, Miaoli 35053, Taiwan; shuchien@ucsd.edu jjchiu@nhri.org.tw.|Institute of Biomedical Engineering, National Tsing Hua University, Hsinchu 30013, Taiwan.|College of Pharmacy, Taipei Medical University, Taipei 110, Taiwan.
Jeng-Jiann
JJ
Chiu
D000818:Animals; D001011:Aorta / Q000166:cytology / Q000502:physiology; D050197:Atherosclerosis / Q000503:physiopathology; D002478:Cells, Cultured; D015536:Down-Regulation; D042783:Endothelial Cells / Q000378:metabolism; D004730:Endothelium, Vascular / Q000166:cytology / Q000502:physiology*; D050993:GATA6 Transcription Factor / Q000235:genetics* / Q000378:metabolism; D006655:Histone Deacetylases / Q000378:metabolism*; D006801:Humans; D051741:Kruppel-Like Transcription Factors / Q000378:metabolism*; D035683:MicroRNAs / Q000378:metabolism*; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000378:metabolism; D051381:Rats; D000072482:Retinoic Acid Receptor alpha / Q000235:genetics / Q000378:metabolism*; D047490:Retinoid X Receptor alpha / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000235:genetics; D013314:Stress, Mechanical; D019010:Vascular Cell Adhesion Molecule-1 / Q000235:genetics / Q000378:metabolism
D050993:GATA6 Transcription Factor; C096161:KLF2 protein, human; D051741:Kruppel-Like Transcription Factors; C547183:MIRN10 microRNA, human; C000603309:MIRN10 microRNA, rat; D035683:MicroRNAs; D034741:RNA, Small Interfering; D000072482:Retinoic Acid Receptor alpha; D047490:Retinoid X Receptor alpha; D019010:Vascular Cell Adhesion Molecule-1; D006655:Histone Deacetylases
endothelial cells; histone deacetylase; hormone receptor; microRNA; shear stress