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Isolation of Mouse Interstitial Valve Cells to Study the Calcification of the Aortic Valve In Vitro
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Pharmacological Enhancement of Integrated Stress Response Confers Protection in Calcific Aortic Valve Disease

Libo Wang1, Xulei Duan1, Huibing Liu1

  • 1Department of Cardiology, Life Science Research Center, The First Affiliated Hospital of Xinxiang Medical University, Xinxiang, Henan, China.

JACC. Basic to Translational Science
|December 16, 2025
PubMed

Insights

Nox4 and integrated stress response (ISR) signaling are implicated in calcific aortic valve disease (CAVD). Enhancing ISR pharmacologically may offer a novel therapeutic strategy for CAVD.

Area of Science:

  • Cardiovascular Biology
  • Molecular Medicine
  • Integrative Physiology

Background:

  • Nox4 and integrated stress response (ISR) signaling (eIF2α/ATF4) protect against heart injury.
  • The role of Nox4 and ISR in calcific aortic valve disease (CAVD) is not well understood.

Purpose of the Study:

  • To investigate the involvement of Nox4 and ISR in CAVD pathogenesis.
  • To explore the therapeutic potential of modulating ISR in CAVD.

Main Methods:

  • Examined ATF4 and Nox4 expression in porcine aortic valve interstitial cells (AVICs) and human CAVD tissues.
  • Utilized Nox4 knockdown and overexpression models in AVICs.
  • Administered ISR activators (Guanabenz, Sephin1) in animal models of CAVD (rabbits, mice).

Main Results:

  • ATF4 and Nox4 were upregulated in CAVD.
  • Nox4 knockdown exacerbated CAVD, while overexpression suppressed it by modulating ISR.
  • ISR activators attenuated AVIC osteoblastic differentiation and mitigated CAVD in vivo.

Conclusions:

  • Nox4 and ISR play critical roles in CAVD development.
  • Pharmacological enhancement of ISR represents a promising therapeutic avenue for CAVD.
Keywords:
ATF4Nox4aortic valveapoptosiscalcificationreactive oxygen species

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