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Potential Role of H-Ferritin in Mitigating Valvular Mineralization

Katalin Éva Sikura1,2, László Potor1,2, Tamás Szerafin2,3

  • 1From the HAS-UD Vascular Biology and Myocardial Pathophysiology Research Group, Hungarian, Academy of Sciences, Debrecen (K.É.S., L.P., M.O., N.P., G.B., J.B.), Faculty of Medicine, University of Debrecen, Hungary.

Arteriosclerosis, Thrombosis, and Vascular Biology
|February 1, 2019
PubMed

Insights

Iron metabolism, specifically H-ferritin, mitigates calcific aortic valve disease by preventing mineralization and inflammation. Inducing H-ferritin may offer a novel therapeutic approach for valvular mineralization.

Area of Science:

  • Biochemistry
  • Cardiovascular Biology
  • Mineral Metabolism

Background:

  • Calcific aortic valve disease (CAVD) is prevalent in the elderly and those with chronic kidney disease.
  • The role of iron metabolism in CAVD pathogenesis remains incompletely understood.
  • Valvular interstitial cells (VICs) are key players in aortic valve mineralization.

Purpose of the Study:

  • To investigate the role of iron metabolism, particularly H-ferritin, in the pathogenesis of CAVD.
  • To explore the therapeutic potential of modulating iron metabolism in CAVD.

Main Methods:

  • Cultured VICs from stenotic aortic valves were treated with phosphate to induce mineralization.
  • H-ferritin induction was assessed via biochemical assays and gene/protein expression analysis.
  • Phosphate uptake, pyrophosphate generation, and transcription factor activity (RUNX2, Sox9) were measured.
  • In vivo effects were studied using a mouse model and histological analysis of human valves.
  • The ferroxidase activity of H-ferritin was evaluated using ceruloplasmin.

Main Results:

  • Phosphate induced mineralization and osteoblastic transdifferentiation in VICs.
  • Iron, via H-ferritin induction, abrogated phosphate-induced mineralization by reducing phosphate uptake and cellular accumulation.
  • H-ferritin decreased alkaline phosphatase (ALP) and osteocalcin secretion, repressed phosphate transporters (Pit1, Pit2), and reduced nuclear RUNX2 accumulation.
  • H-ferritin enhanced nuclear Sox9 localization and increased pyrophosphate generation via ENPP2 upregulation.
  • Treatment with 3H-1,2-dithiole-3-thione mimicked these effects by inducing H-ferritin.
  • Histological analysis showed high H-ferritin expression in non-calcified regions of stenotic valves, correlating with reduced inflammation (TNF-α, IL-1β).

Conclusions:

  • H-ferritin plays a protective role against valvular mineralization and osteoblastic differentiation in CAVD.
  • Ferritin's ferroxidase activity is crucial for its inhibitory function.
  • Inducing H-ferritin expression, potentially with agents like 3H-1,2-dithiole-3-thione, represents a promising therapeutic strategy for CAVD.

Keywords:
arteriosclerosischronic kidney diseasephosphatestenosisvascular calcification

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