Pharmacological Enhancement of Integrated Stress Response Confers Protection in Calcific Aortic Valve Disease

  • JACC Basic Transl Sci. 2025 Dec 15;11(1):101433. doi: 10.1016/j.jacbts.2025.101433.
Libo Wang  1 ,  Xulei Duan  1 ,  Huibing Liu  1 ,  Fei Lin  1 ,  Chaoyuan Zhou  1 ,  Katrin Schröder  2 ,  Ajay M Shah  3 ,  Guoan Zhao  4 ,  Min Zhang  5
Affiliations
  • 1. Department of Cardiology, Life Science Research Center, The First Affiliated Hospital of Xinxiang Medical University, Xinxiang, Henan, China.
  • 2. Institute for Cardiovascular Physiology, Goethe-University, Frankfurt, Germany.
  • 3. King's College London British Heart Foundation Centre of Research Excellence, School of Cardiovascular and Metabolic Medicine & Sciences, London, United Kingdom.
  • 4. Department of Cardiology, Life Science Research Center, The First Affiliated Hospital of Xinxiang Medical University, Xinxiang, Henan, China. Electronic address: [email protected].
  • 5. King's College London British Heart Foundation Centre of Research Excellence, School of Cardiovascular and Metabolic Medicine & Sciences, London, United Kingdom. Electronic address: [email protected].
PMID: 41401678 DOI: 10.1016/j.jacbts.2025.101433
Abstract

Previous studies have shown that NOX4 activates eIF2α/ATF4 signaling during the integrated stress response (ISR) and protects heart injury. However, their roles in calcific aortic valve disease (CAVD) remain unclear. Here, we show that both ATF4 and NOX4 are up-regulated in porcine aortic valve interstitial cells (AVIC) and in human aortic valves with CAVD. NOX4 knockdown promotes while NOX4 overexpression suppresses CAVD by modulating ISR. Importantly, ISR activators Guanabenz and Sephin1 effectively attenuate AVIC osteoblastic-like differentiation and mitigate CAVD in rabbits and mice, respectively. These findings highlight that pharmacological enhancement of the ISR is a promising therapeutic strategy for CAVD.

Keywords
ATF4; Nox4; aortic valve; apoptosis; calcification; reactive oxygen species.
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