Potential Role of H-Ferritin in Mitigating Valvular Mineralization

Arterioscler Thromb Vasc Biol. 2019 Mar;39(3):413-431. doi: 10.1161/ATVBAHA.118.312191.


Objective- Calcific aortic valve disease is a prominent finding in elderly and in patients with chronic kidney disease. We investigated the potential role of iron metabolism in the pathogenesis of calcific aortic valve disease. Approach and Results- Cultured valvular interstitial cells of stenotic aortic valve with calcification from patients undergoing valve replacement exhibited significant susceptibility to mineralization/osteoblastic transdifferentiation in response to phosphate. This process was abrogated by iron via induction of H-ferritin as reflected by lowering ALP and osteocalcin secretion and preventing extracellular calcium deposition. Cellular phosphate uptake and accumulation of lysosomal phosphate were decreased. Accordingly, expression of phosphate transporters Pit1 and Pit2 were repressed. Translocation of ferritin into lysosomes occurred with high phosphate-binding capacity. Importantly, ferritin reduced nuclear accumulation of RUNX2 (Runt-related transcription factor 2), and as a reciprocal effect, it enhanced nuclear localization of transcription factor Sox9 (SRY [sex-determining region Y]-box 9). Pyrophosphate generation was also increased via upregulation of ENPP2 (ectonucleotide pyrophosphatase/phosphodiesterase-2). 3H-1, 2-dithiole-3-thione mimicked these beneficial effects in valvular interstitial cell via induction of H-ferritin. Ferroxidase activity of H-ferritin was essential for this function, as ceruloplasmin exhibited similar inhibitory functions. Histological analysis of stenotic aortic valve revealed high expression of H-ferritin without iron accumulation and its relative dominance over ALP in noncalcified regions. Increased expression of H-ferritin accompanied by elevation of TNF-α (tumor necrosis factor-α) and IL-1β (interleukin-1β) levels, inducers of H-ferritin, corroborates the essential role of ferritin/ferroxidase via attenuating inflammation in calcific aortic valve disease. Conclusions- Our results indicate that H-ferritin is a stratagem in mitigating valvular mineralization/osteoblastic differentiation. Utilization of 3H-1, 2-dithiole-3-thione to induce ferritin expression may prove a novel therapeutic potential in valvular mineralization.

Keywords: arteriosclerosis; chronic kidney disease; phosphate; stenosis; vascular calcification.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aortic Valve / metabolism
  • Aortic Valve / pathology
  • Aortic Valve Stenosis / metabolism*
  • Aortic Valve Stenosis / pathology
  • Apoferritins / antagonists & inhibitors
  • Apoferritins / pharmacology
  • Apoferritins / physiology*
  • Biological Transport
  • Cell Nucleus / metabolism
  • Cells, Cultured
  • Core Binding Factor Alpha 1 Subunit / biosynthesis
  • Core Binding Factor Alpha 1 Subunit / genetics
  • Endothelial Cells / metabolism
  • Gene Expression Regulation
  • Interleukin-1beta / biosynthesis
  • Interleukin-1beta / genetics
  • Ion Channels / biosynthesis
  • Iron / pharmacology
  • Lysosomes / metabolism
  • Phosphates / metabolism
  • Phosphoric Diester Hydrolases / biosynthesis
  • Phosphoric Diester Hydrolases / genetics
  • SOX9 Transcription Factor / metabolism
  • Thiones / pharmacology
  • Thiophenes / pharmacology
  • Tumor Necrosis Factor-alpha / biosynthesis
  • Tumor Necrosis Factor-alpha / genetics
  • Vascular Calcification / metabolism*
  • Vascular Calcification / pathology


  • Core Binding Factor Alpha 1 Subunit
  • Interleukin-1beta
  • Ion Channels
  • Phosphates
  • RUNX2 protein, human
  • SOX9 Transcription Factor
  • SOX9 protein, human
  • Thiones
  • Thiophenes
  • Tumor Necrosis Factor-alpha
  • Apoferritins
  • Iron
  • Phosphoric Diester Hydrolases
  • alkylglycerophosphoethanolamine phosphodiesterase
  • 1,2-dithiol-3-thione