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Cardiovascular Engineering and Technology

, Volume 9, Issue 2, pp 141–150 | Cite as

Mechanosensitive microRNA-181b Regulates Aortic Valve Endothelial Matrix Degradation by Targeting TIMP3

  • Jack M. Heath
  • Joan Fernandez Esmerats
  • Lucky Khambouneheuang
  • Sandeep Kumar
  • Rachel Simmons
  • Hanjoong Jo
Article

Abstract

Calcific aortic valve disease (CAVD) is a major cause of morbidity in the aging population, but the underlying mechanisms of its progression remain poorly understood. Aortic valve calcification preferentially occurs on the fibrosa, which is subjected to disturbed flow. The side-specific progression of the disease is characterized by inflammation, calcific lesions, and extracellular matrix (ECM) degradation. Here, we explored the role of mechanosensitive microRNA-181b and its downstream targets in human aortic valve endothelial cells (HAVECs). Mechanistically, miR-181b is upregulated in OS and fibrosa, and it targets TIMP3, SIRT1, and GATA6, correlated with increased gelatinase/MMP activity. Overexpression of miR-181b led to decreased TIMP3 and exacerbated MMP activity as shown by gelatinase assay, and miR-181b inhibition decreased gelatinase activity through the repression of TIMP3 levels. Luciferase assay showed specific binding of miR-181b to the TIMP3 gene. Overexpression of miR-181b in HAVECs subjected to either LS or OS increased MMP activity, and miR-181b inhibition abrogated shear-sensitive MMP activity. These studies suggest that targeting this shear-dependent miRNA may provide a novel noninvasive treatment for CAVD.

Keywords

microRNA Aortic valve Extracellular matrix Matrix metalloproteinase Shear stress Endothelium 

Notes

Funding

This study was funded by NIH (R01HL114772) as well as NHLBI Grants (HL119798, HL113451, HL095070 and HL124879).

Conflict of Interest

All the authors declare that they have no conflict of interest.

Ethical Approval

All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.

Informed consent

Informed consent was obtained from all individual participants included in the study.

Supplementary material

13239_2017_296_MOESM1_ESM.docx (111 kb)
Supplementary Table I List of quantitative PCR primers used in analysis of gene targets of miRNA-181b (DOCX 112 kb)

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Copyright information

© Biomedical Engineering Society 2017

Authors and Affiliations

  • Jack M. Heath
    • 1
  • Joan Fernandez Esmerats
    • 1
  • Lucky Khambouneheuang
    • 1
  • Sandeep Kumar
    • 1
  • Rachel Simmons
    • 1
  • Hanjoong Jo
    • 1
    • 2
  1. 1.Coulter Department of Biomedical EngineeringEmory University and Georgia Institute of TechnologyAtlantaUSA
  2. 2.Department of CardiologyEmory UniversityAtlantaUSA

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