Shear-sensitive microRNA-34a modulates flow-dependent regulation of endothelial inflammation.
Although many studies have described the roles of microRNAs (miRNAs) in the modulation of the endothelial response to shear stress, the mechanisms remain incompletely understood. Here, we demonstrate that miR-34a expression in endothelial cells was downregulated by atheroprotective physiological high shear stress (HSS), whereas it was upregulated by atheroprone oscillatory shear stress (OSS). Blockade of endogenous miR-34a dramatically decreased basal vascular cell adhesion molecule-1 (VCAM-1) and intercellular adhesion molecule-1 (ICAM-1) protein expression levels. Conversely, miR-34a overexpression increased the protein levels of VCAM-1 and ICAM-1, consequently promoting monocyte adhesion to endothelial cells. Furthermore, miR-34a overexpression attenuated HSS-mediated suppression of VCAM-1 protein expression on endothelial cells, but promoted HSS-induced ICAM-1 expression. In addition, the OSS induction of endothelial cell VCAM-1 and ICAM-1 was suppressed by using an miR-34a inhibitor, which led to a reduction of monocyte adhesion to endothelial cells. Mechanistically, sirtuin 1 overexpression partially prevented miR-34a-induced VCAM-1 and ICAM-1 expression. Subsequent investigation demonstrated that miR-34a increased nuclear factor κB (NF-κB) p65 subunit (also known as RelA) acetylation (on residue Lys310), and silencing NF-κB signaling reduced miR-34a-induced VCAM-1 and ICAM-1 protein expression. These results demonstrate that miR-34a is involved in the flow-dependent regulation of endothelial inflammation.
Division of Cardiology, First Affiliated Hospital of Sun Yat-sen University, Guangzhou 510080, China Key Laboratory on Assisted Circulation, Ministry of Health, Guangzhou 510080, China.
Wendong
W
Fan
Division of Cardiology, First Affiliated Hospital of Sun Yat-sen University, Guangzhou 510080, China Key Laboratory on Assisted Circulation, Ministry of Health, Guangzhou 510080, China.
Rong
R
Fang
Division of Cardiology, First Affiliated Hospital of Sun Yat-sen University, Guangzhou 510080, China Key Laboratory on Assisted Circulation, Ministry of Health, Guangzhou 510080, China.
Xiaoyuan
X
Wu
Division of Cardiology, First Affiliated Hospital of Sun Yat-sen University, Guangzhou 510080, China Key Laboratory on Assisted Circulation, Ministry of Health, Guangzhou 510080, China.
Jia
J
Liu
Division of Cardiology, First Affiliated Hospital of Sun Yat-sen University, Guangzhou 510080, China Key Laboratory on Assisted Circulation, Ministry of Health, Guangzhou 510080, China.
Mingzhe
M
Feng
Division of Cardiology, First Affiliated Hospital of Sun Yat-sen University, Guangzhou 510080, China Key Laboratory on Assisted Circulation, Ministry of Health, Guangzhou 510080, China.
Gang
G
Dai
Affiliated Futian Hospital of Guangdong Medical College, Shenzhen 518033, China.
Guojun
G
Chen
Key Laboratory on Assisted Circulation, Ministry of Health, Guangzhou 510080, China Affiliated Futian Hospital of Guangdong Medical College, Shenzhen 518033, China wuguifu@mail.sysu.edu.cn.
Guifu
G
Wu
D002448:Cell Adhesion / Q000235:genetics; D005786:Gene Expression Regulation; D061307:Human Umbilical Vein Endothelial Cells / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D007249:Inflammation / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D018799:Intercellular Adhesion Molecule-1 / Q000096:biosynthesis / Q000235:genetics; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D009000:Monocytes / Q000378:metabolism / Q000473:pathology; D033081:Shear Strength; D015398:Signal Transduction; D051996:Transcription Factor RelA / Q000235:genetics / Q000378:metabolism; D019010:Vascular Cell Adhesion Molecule-1 / Q000096:biosynthesis / Q000235:genetics
C573420:ICAM1 protein, human; C522425:MIRN34 microRNA, human; D035683:MicroRNAs; C498143:RELA protein, human; D051996:Transcription Factor RelA; D019010:Vascular Cell Adhesion Molecule-1; D018799:Intercellular Adhesion Molecule-1
Endothelial cells; Inflammation; MicroRNA; SIRT1; Shear stress