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Isolation and Characterization of Primary Rat Valve Interstitial Cells: A New Model to Study Aortic Valve Calcification
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Isolation and Characterization of Primary Rat Valve Interstitial Cells: A New Model to Study Aortic Valve Calcification

Published on: November 20, 2017

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Histone deacetylase 6 reduction promotes aortic valve calcification via an endoplasmic reticulum stress-mediated

Zurong Fu1, Fei Li2, Liangliang Jia1

  • 1Department of Cardiology, The Second Affiliated Hospital, Zhejiang University School of Medicine, Key Lab of Cardiovascular Disease of Zhejiang Province, Hangzhou, Zhejiang, China.

The Journal of Thoracic and Cardiovascular Surgery
|December 24, 2018
PubMed

Insights

Inhibition of HDAC6 promotes aortic valve calcification by activating endoplasmic reticulum stress and the ATF4 pathway. HDAC6 may be a new therapeutic target for preventing and treating aortic valve calcification.

Area of Science:

  • Cardiovascular Biology
  • Molecular Mechanisms of Disease
  • Cellular Pathophysiology

Background:

  • Aortic valve (AoV) calcification involves osteoblastic differentiation of valvular interstitial cells (VICs).
  • Histone deacetylases (HDACs) play a role in vascular disease pathogenesis.
  • The specific role of HDAC6 in AoV calcification requires investigation.

Purpose of the Study:

  • To investigate the role of HDAC6 in the process of aortic valve calcification.
  • To elucidate the molecular pathways involved in HDAC6-mediated AoV calcification.

Main Methods:

  • Analysis of HDAC6 expression and calcified nodules in human AoV tissues from patients with aortic stenosis and controls.
  • Inhibition of HDAC6 in cultured human VICs using tubacin or HDAC6 small interfering RNA (siRNA).
  • Assessment of osteoblastic differentiation, endoplasmic reticulum (ER) stress, and the ATF4 pathway.

Main Results:

  • HDAC6 expression was significantly lower in stenotic AoV tissues compared to controls.
  • HDAC6 inhibition (tubacin or siRNA) promoted VIC osteoblastic differentiation and ER stress.
  • The pro-calcific effect of HDAC6 inhibition was mediated by the ER stress/ATF4 pathway, confirmed by tauroursodeoxycholic acid (TUDCA) and ATF4 siRNA treatments.

Conclusions:

  • HDAC6 inhibition promotes AoV calcification through an ER stress/ATF4-dependent osteogenic pathway.
  • HDAC6 represents a potential novel therapeutic target for preventing and treating AoV calcification.
Abstract

Keywords:
aortic valve calcificationendoplasmic reticulum stresshistone deacetylase 6osteogenesis

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