Objectives: The cellular mechanisms of calcific aortic valve (AV) disease and optimal medications for its treatment are poorly elucidated. Glycogen synthase kinase (GSK)-3β and non-canonical wingless-related integration site (Wnt) signaling play crucial roles in regulating the pathogenesis of valvular interstitial cell (VIC) calcification. Histone acetylation was found to regulate VIC calcification. However, whether histone deacetylases (HDACs) modulate the pathophysiology of AV calcification is unclear. Different HDAC isoforms have dissimilar cardiovascular effects. We hypothesized that distinctive HDAC inhibitors modulate runt-related transcription factor 2 (RUNX2) in aortic VICs through the regulation of Wnt signaling. Methods: Western blotting, real-time polymerase chain reaction, and proliferation assay were used to analyze osteogenesis marker expression, Wnt signaling, bone morphogenetic protein (BMP) signaling, and proliferation in porcine VICs treated with osteogenic (OST) medium alone or in combination with HDAC inhibitors. Results: VICs treated with OST medium for 5 days exhibited higher RUNX2 and GSK-3β expression levels than did control cells. A class I HDAC inhibitor (MS-275 at 1 μM) reduced the RUNX2 mRNA and protein expression levels and alkaline phosphatase activity and downregulated non-canonical Wnt/GSK-3β signaling, canonical Wnt/β-catenin signaling, and BMP signaling. By contrast, a combined class IIa (MC1568) and IIb HDAC (tubacin) inhibitor (0.1 μM) increased RUNX2 expression. MS-275, MC1568, and tubacin reduced VIC proliferation; however, the extent of reduction differed. MS-275 reduced RUNX2 and osteocalcin expression in VICs treated with OST medium for an extended period (14 days). Conclusions: MS-275 critically regulates RUNX2 transactivation in VICs through both canonical and non-canonical Wnt signaling pathways.

Original languageEnglish
Article numberAJTR0089749
Pages (from-to)744-754
Number of pages11
JournalAmerican Journal of Translational Research
Issue number2
Publication statusPublished - Jan 1 2019


  • Calcific aortic valvular disease
  • Glycogen synthase kinase 3β
  • MS-275
  • RUNX2
  • Wnt
  • β-catenin

ASJC Scopus subject areas

  • Molecular Medicine
  • Clinical Biochemistry
  • Cancer Research


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