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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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Herpud1 deficiency alleviates homocysteine-induced aortic valve calcification

Wenqing Xie1,2, Yue Shan3, Zhuonan Wu4

  • 1Department of Cardiology, Shaoxing People's Hospital, Shaoxing Hospital, Zhejiang University School of Medicine, Shaoxing, 312000, Zhejiang, China.

Cell Biology and Toxicology
|February 6, 2023
PubMed

Insights

Homocysteine (hcy) promotes calcific aortic valve disease (CAVD) by increasing Herpud1 expression via endoplasmic reticulum stress (ERS). Silencing Herpud1 or inhibiting ERS reduces CAVD progression, offering a potential therapeutic strategy.

Area of Science:

  • Molecular Biology
  • Cardiovascular Research
  • Cellular Pathophysiology

Background:

  • Calcific aortic valve disease (CAVD) has high morbidity and mortality with limited treatment options.
  • Homocysteine (hcy) is implicated in CAVD progression.
  • The role of endoplasmic reticulum stress (ERS) and specific proteins in hcy-induced CAVD is not fully understood.

Purpose of the Study:

  • To investigate the role of the hcy-inducible ERS protein Herpud1 in hcy-induced CAVD.
  • To evaluate Herpud1 as a potential therapeutic target for CAVD.

Main Methods:

  • Utilized low-density lipoprotein receptor (LDLR) and Herpud1 double knockout mice fed a high methionine diet (HMD) to study in vivo CAVD.
  • Assessed aortic valve calcification, ERS activation, autophagy, and osteogenic differentiation of aortic valve interstitial cells (AVICs).
  • Investigated Herpud1's role in hcy-related AVIC osteogenic differentiation in vitro by manipulating Herpud1 expression.

Main Results:

  • Herpud1 was highly expressed in calcified human and mouse aortic valves and AVICs.
  • Hcy increased Herpud1 expression via ERS, promoting CAVD; Herpud1 deficiency inhibited hcy-induced CAVD.
  • Herpud1 silencing activated autophagy, inhibiting hcy-induced AVIC osteogenic differentiation; ERS inhibition (4-PBA) reduced aortic valve calcification.

Conclusions:

  • Herpud1 is upregulated in hcy-related CAVD through the ERS pathway.
  • Herpud1 deficiency or inhibition mitigates hcy-induced CAVD progression.
  • Herpud1 silencing or inhibition represents a promising therapeutic strategy for CAVD.
Abstract

Keywords:
4-phenyl butyric acidAutophagyCalcific aortic valve diseaseEndoplasmic reticulum stressHerpud1Homocysteine

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