MicroRNA mediation of endothelial inflammatory response to smooth muscle cells and its inhibition by atheroprotective shear stress

Li Jing Chen, Li Chuang, Yi Hsuan Huang, Jing Zhou, Seh Hong Lim, Chih I. Lee, Wei Wen Lin, Ting Er Lin, Wei Li Wang, Linyi Chen, Shu Chien, Jeng Jiann Chiu

Research output: Contribution to journalArticlepeer-review

55 Citations (Scopus)


Rationale: 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. Methods and 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/cm2) 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.

Original languageEnglish
Pages (from-to)1157-1169
Number of pages13
JournalCirculation Research
Issue number7
Publication statusPublished - Mar 27 2015
Externally publishedYes


  • Atherosclerosis
  • Endothelial cell
  • microRNA
  • Shear stress
  • Smooth muscle myocytes

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine


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