Related Experiment Video

Updated: Nov 7, 2025

Isolation of Mouse Interstitial Valve Cells to Study the Calcification of the Aortic Valve In Vitro
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Isolation of Mouse Interstitial Valve Cells to Study the Calcification of the Aortic Valve In Vitro

Published on: May 10, 2021

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Heme-Mediated Activation of the Nrf2/HO-1 Axis Attenuates Calcification of Valve Interstitial Cells

Enikő Balogh1, Arpan Chowdhury1,2, Haneen Ababneh1,2

  • 1MTA-DE Lendület Vascular Pathophysiology Research Group, Research Centre for Molecular Medicine, Faculty of Medicine, University of Debrecen, 4032 Debrecen, Hungary.

Biomedicines
|April 30, 2021
PubMed

Insights

Heme activates the Nrf2/HO-1 pathway, inhibiting calcific aortic valve stenosis by preventing calcium deposition in heart cells. This protective effect is mediated by heme breakdown products and ferritin.

Area of Science:

  • Cardiovascular Biology
  • Cellular Biology
  • Biochemistry

Background:

  • Calcific aortic valve stenosis (CAVS) involves fibro-calcific remodeling of aortic valves.
  • Valvular interstitial cells (VICs) differentiate into osteoblast-like cells, a process influenced by reactive oxygen species.
  • The Nuclear factor erythroid 2-related factor 2 (Nrf2) pathway and its target gene, Heme oxygenase-1 (HO-1), play a protective role in valve calcification.

Purpose of the Study:

  • To investigate the role of the Nrf2/HO-1 axis in the osteogenic differentiation and calcification of VICs.
  • To determine if heme can inhibit VIC calcification and elucidate the underlying mechanisms.

Main Methods:

  • Human VICs were induced to undergo osteogenic differentiation using a high phosphate and calcium medium (OM).
  • The effect of heme on calcium deposition, alkaline phosphatase, and osteocalcin (OCN) expression was assessed.
  • Nrf2 transcriptional activity and HO-1 enzyme activity were inhibited to evaluate their role in heme's anti-calcification effects.

Main Results:

  • Heme significantly inhibited calcium deposition and the expression of alkaline phosphatase and OCN in VICs.
  • Heme treatment led to increased expression of Nrf2 and HO-1 in VICs.
  • The anti-calcification effects of heme were abolished upon blocking Nrf2 transcriptional activity or HO-1 enzyme activity.
  • Heme catabolism products (bilirubin, carbon monoxide, iron) and ferritin also inhibited VIC calcification and OCN expression.

Conclusions:

  • Heme-mediated activation of the Nrf2/HO-1 pathway effectively inhibits VIC calcification.
  • The anti-calcific properties of heme are attributed to the downstream products of HO-1-catalyzed heme degradation and ferritin.

Keywords:
Nrf2ferritinhemeheme oxygenase-1 (HO-1)osteogenic differentiationvalve calcificationvalve interstitial cell (VIC)

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