title: MicroRNA mediation of endothelial inflammatory response to smooth muscle cells and its inhibition by atheroprotective shear stress.
abstract: BACKGROUND
  In atherosclerotic lesions, synthetic smooth muscle cells (sSMCs) induce aberrant microRNA (miR) profiles in endothelial cells (ECs) under flow stagnation. Increase in shear stress induces favorable miR modulation to mitigate sSMC-induced inflammation.
  
  
  OBJECTIVE
  To address the role of miRs in sSMC-induced EC inflammation and its inhibition by shear stress.
  
  
  RESULTS
  Coculturing ECs with sSMCs under static condition causes initial increases of 4 anti-inflammatory miRs (146a/708/451/98) in ECs followed by decreases below basal levels at 7 days; the increases for miR-146a/708 peaked at 24 hours and those for miR-451/98 lasted for only 6 to 12 hours. Shear stress (12 dynes/cm(2)) to cocultured ECs for 24 hours augments these 4 miR expressions. In vivo, these 4 miRs are highly expressed in neointimal ECs in injured arteries under physiological levels of flow, but not expressed under flow stagnation. MiR-146a, miR-708, miR-451, and miR-98 target interleukin-1 receptor-associated kinase, inhibitor of nuclear factor-κB kinase subunit-γ, interleukin-6 receptor, and conserved helix-loop-helix ubiquitous kinase, respectively, to inhibit nuclear factor-κB signaling, which exerts negative feedback control on the biogenesis of these miRs. Nuclear factor-E2-related factor (Nrf)-2 is critical for shear-induction of miR-146a in cocultured ECs. Silencing either Nrf-2 or miR-146a led to increased neointima formation of injured rat carotid artery under physiological levels of flow. Overexpressing miR-146a inhibits neointima formation of rat or mouse carotid artery induced by injury or flow cessation.
  
  
  CONCLUSIONS
  Nrf-2-mediated miR-146a expression is augmented by atheroprotective shear stress in ECs adjacent to sSMCs to inhibit neointima formation of injured arteries.
authors.affiliation: From the Institute of Cellular and System Medicine, National Health Research Institutes, Miaoli, Taiwan (L.-J.C., Li Chuang, Y.-H.H., S.H.L., C.-I.L., T.-E.L., W.-L.W., J.-J.C.); Institute of Molecular Medicine (Linyi Chen) and Institute of Biomedical Engineering (J.-J.C.), National Tsing Hua University, Hsinchu, Taiwan; Department of Physiology and Pathophysiology, Basic Medical College, Peking University, Beijing, China (J.Z.); Department of Cardiology, Internal Medicine, Taichung Veterans General Hospital, Taichung, Taiwan (W.-W.L.); and Department of Bioengineering and Institute of Engineering in Medicine, University of California, San Diego, La Jolla (S.C.).
authors.forename: Li-Jing
authors.initials: LJ
authors.lastname: Chen
authors.affiliation: From the Institute of Cellular and System Medicine, National Health Research Institutes, Miaoli, Taiwan (L.-J.C., Li Chuang, Y.-H.H., S.H.L., C.-I.L., T.-E.L., W.-L.W., J.-J.C.); Institute of Molecular Medicine (Linyi Chen) and Institute of Biomedical Engineering (J.-J.C.), National Tsing Hua University, Hsinchu, Taiwan; Department of Physiology and Pathophysiology, Basic Medical College, Peking University, Beijing, China (J.Z.); Department of Cardiology, Internal Medicine, Taichung Veterans General Hospital, Taichung, Taiwan (W.-W.L.); and Department of Bioengineering and Institute of Engineering in Medicine, University of California, San Diego, La Jolla (S.C.).
authors.forename: Li
authors.initials: L
authors.lastname: Chuang
authors.affiliation: From the Institute of Cellular and System Medicine, National Health Research Institutes, Miaoli, Taiwan (L.-J.C., Li Chuang, Y.-H.H., S.H.L., C.-I.L., T.-E.L., W.-L.W., J.-J.C.); Institute of Molecular Medicine (Linyi Chen) and Institute of Biomedical Engineering (J.-J.C.), National Tsing Hua University, Hsinchu, Taiwan; Department of Physiology and Pathophysiology, Basic Medical College, Peking University, Beijing, China (J.Z.); Department of Cardiology, Internal Medicine, Taichung Veterans General Hospital, Taichung, Taiwan (W.-W.L.); and Department of Bioengineering and Institute of Engineering in Medicine, University of California, San Diego, La Jolla (S.C.).
authors.forename: Yi-Hsuan
authors.initials: YH
authors.lastname: Huang
authors.affiliation: From the Institute of Cellular and System Medicine, National Health Research Institutes, Miaoli, Taiwan (L.-J.C., Li Chuang, Y.-H.H., S.H.L., C.-I.L., T.-E.L., W.-L.W., J.-J.C.); Institute of Molecular Medicine (Linyi Chen) and Institute of Biomedical Engineering (J.-J.C.), National Tsing Hua University, Hsinchu, Taiwan; Department of Physiology and Pathophysiology, Basic Medical College, Peking University, Beijing, China (J.Z.); Department of Cardiology, Internal Medicine, Taichung Veterans General Hospital, Taichung, Taiwan (W.-W.L.); and Department of Bioengineering and Institute of Engineering in Medicine, University of California, San Diego, La Jolla (S.C.).
authors.forename: Jing
authors.initials: J
authors.lastname: Zhou
authors.affiliation: From the Institute of Cellular and System Medicine, National Health Research Institutes, Miaoli, Taiwan (L.-J.C., Li Chuang, Y.-H.H., S.H.L., C.-I.L., T.-E.L., W.-L.W., J.-J.C.); Institute of Molecular Medicine (Linyi Chen) and Institute of Biomedical Engineering (J.-J.C.), National Tsing Hua University, Hsinchu, Taiwan; Department of Physiology and Pathophysiology, Basic Medical College, Peking University, Beijing, China (J.Z.); Department of Cardiology, Internal Medicine, Taichung Veterans General Hospital, Taichung, Taiwan (W.-W.L.); and Department of Bioengineering and Institute of Engineering in Medicine, University of California, San Diego, La Jolla (S.C.).
authors.forename: Seh Hong
authors.initials: SH
authors.lastname: Lim
authors.affiliation: From the Institute of Cellular and System Medicine, National Health Research Institutes, Miaoli, Taiwan (L.-J.C., Li Chuang, Y.-H.H., S.H.L., C.-I.L., T.-E.L., W.-L.W., J.-J.C.); Institute of Molecular Medicine (Linyi Chen) and Institute of Biomedical Engineering (J.-J.C.), National Tsing Hua University, Hsinchu, Taiwan; Department of Physiology and Pathophysiology, Basic Medical College, Peking University, Beijing, China (J.Z.); Department of Cardiology, Internal Medicine, Taichung Veterans General Hospital, Taichung, Taiwan (W.-W.L.); and Department of Bioengineering and Institute of Engineering in Medicine, University of California, San Diego, La Jolla (S.C.).
authors.forename: Chih-I
authors.initials: CI
authors.lastname: Lee
authors.affiliation: From the Institute of Cellular and System Medicine, National Health Research Institutes, Miaoli, Taiwan (L.-J.C., Li Chuang, Y.-H.H., S.H.L., C.-I.L., T.-E.L., W.-L.W., J.-J.C.); Institute of Molecular Medicine (Linyi Chen) and Institute of Biomedical Engineering (J.-J.C.), National Tsing Hua University, Hsinchu, Taiwan; Department of Physiology and Pathophysiology, Basic Medical College, Peking University, Beijing, China (J.Z.); Department of Cardiology, Internal Medicine, Taichung Veterans General Hospital, Taichung, Taiwan (W.-W.L.); and Department of Bioengineering and Institute of Engineering in Medicine, University of California, San Diego, La Jolla (S.C.).
authors.forename: Wei-Wen
authors.initials: WW
authors.lastname: Lin
authors.affiliation: From the Institute of Cellular and System Medicine, National Health Research Institutes, Miaoli, Taiwan (L.-J.C., Li Chuang, Y.-H.H., S.H.L., C.-I.L., T.-E.L., W.-L.W., J.-J.C.); Institute of Molecular Medicine (Linyi Chen) and Institute of Biomedical Engineering (J.-J.C.), National Tsing Hua University, Hsinchu, Taiwan; Department of Physiology and Pathophysiology, Basic Medical College, Peking University, Beijing, China (J.Z.); Department of Cardiology, Internal Medicine, Taichung Veterans General Hospital, Taichung, Taiwan (W.-W.L.); and Department of Bioengineering and Institute of Engineering in Medicine, University of California, San Diego, La Jolla (S.C.).
authors.forename: Ting-Er
authors.initials: TE
authors.lastname: Lin
authors.affiliation: From the Institute of Cellular and System Medicine, National Health Research Institutes, Miaoli, Taiwan (L.-J.C., Li Chuang, Y.-H.H., S.H.L., C.-I.L., T.-E.L., W.-L.W., J.-J.C.); Institute of Molecular Medicine (Linyi Chen) and Institute of Biomedical Engineering (J.-J.C.), National Tsing Hua University, Hsinchu, Taiwan; Department of Physiology and Pathophysiology, Basic Medical College, Peking University, Beijing, China (J.Z.); Department of Cardiology, Internal Medicine, Taichung Veterans General Hospital, Taichung, Taiwan (W.-W.L.); and Department of Bioengineering and Institute of Engineering in Medicine, University of California, San Diego, La Jolla (S.C.).
authors.forename: Wei-Li
authors.initials: WL
authors.lastname: Wang
authors.affiliation: From the Institute of Cellular and System Medicine, National Health Research Institutes, Miaoli, Taiwan (L.-J.C., Li Chuang, Y.-H.H., S.H.L., C.-I.L., T.-E.L., W.-L.W., J.-J.C.); Institute of Molecular Medicine (Linyi Chen) and Institute of Biomedical Engineering (J.-J.C.), National Tsing Hua University, Hsinchu, Taiwan; Department of Physiology and Pathophysiology, Basic Medical College, Peking University, Beijing, China (J.Z.); Department of Cardiology, Internal Medicine, Taichung Veterans General Hospital, Taichung, Taiwan (W.-W.L.); and Department of Bioengineering and Institute of Engineering in Medicine, University of California, San Diego, La Jolla (S.C.).
authors.forename: Linyi
authors.initials: L
authors.lastname: Chen
authors.affiliation: From the Institute of Cellular and System Medicine, National Health Research Institutes, Miaoli, Taiwan (L.-J.C., Li Chuang, Y.-H.H., S.H.L., C.-I.L., T.-E.L., W.-L.W., J.-J.C.); Institute of Molecular Medicine (Linyi Chen) and Institute of Biomedical Engineering (J.-J.C.), National Tsing Hua University, Hsinchu, Taiwan; Department of Physiology and Pathophysiology, Basic Medical College, Peking University, Beijing, China (J.Z.); Department of Cardiology, Internal Medicine, Taichung Veterans General Hospital, Taichung, Taiwan (W.-W.L.); and Department of Bioengineering and Institute of Engineering in Medicine, University of California, San Diego, La Jolla (S.C.).
authors.forename: Shu
authors.initials: S
authors.lastname: Chien
authors.affiliation: From the Institute of Cellular and System Medicine, National Health Research Institutes, Miaoli, Taiwan (L.-J.C., Li Chuang, Y.-H.H., S.H.L., C.-I.L., T.-E.L., W.-L.W., J.-J.C.); Institute of Molecular Medicine (Linyi Chen) and Institute of Biomedical Engineering (J.-J.C.), National Tsing Hua University, Hsinchu, Taiwan; Department of Physiology and Pathophysiology, Basic Medical College, Peking University, Beijing, China (J.Z.); Department of Cardiology, Internal Medicine, Taichung Veterans General Hospital, Taichung, Taiwan (W.-W.L.); and Department of Bioengineering and Institute of Engineering in Medicine, University of California, San Diego, La Jolla (S.C.). jjchiu@nhri.org.tw.
authors.forename: Jeng-Jiann
authors.initials: JJ
authors.lastname: Chiu
mesh_terms: D000818:Animals; D001011:Aorta; D050197:Atherosclerosis / Q000235:genetics / Q000517:prevention & control*; D020212:Carotid Artery Injuries / Q000235:genetics / Q000473:pathology; D002450:Cell Communication; D002478:Cells, Cultured; D018920:Coculture Techniques; D006224:Cricetinae; D016207:Cytokines / Q000096:biosynthesis* / Q000235:genetics; D042783:Endothelial Cells / Q000502:physiology*; D004730:Endothelium, Vascular / Q000503:physiopathology*; D005260:Female; D005786:Gene Expression Regulation; D018056:Hemorheology; D007249:Inflammation / Q000235:genetics*; D016023:Integrins / Q000502:physiology; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D035683:MicroRNAs / Q000502:physiology*; D009131:Muscle, Smooth, Vascular / Q000503:physiopathology*; D032389:Myocytes, Smooth Muscle / Q000502:physiology*; D051267:NF-E2-Related Factor 2 / Q000502:physiology; D016328:NF-kappa B / Q000378:metabolism; D058426:Neointima / Q000235:genetics* / Q000378:metabolism; D034622:RNA Interference; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D016207:Cytokines; D016023:Integrins; C542542:MIRN146 microRNA, human; D035683:MicroRNAs; D051267:NF-E2-Related Factor 2; D016328:NF-kappa B; C495635:NFE2L2 protein, human
keywords: atherosclerosis; endothelial cell; microRNA; shear stress; smooth muscle myocytes