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      HDAC I inhibitor regulates RUNX2 transactivation through canonical and non-canonical Wnt signaling in aortic valvular interstitial cells

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          Abstract

          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.

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          Author and article information

          Journal
          Am J Transl Res
          Am J Transl Res
          ajtr
          American Journal of Translational Research
          e-Century Publishing Corporation
          1943-8141
          2019
          15 February 2019
          : 11
          : 2
          : 744-754
          Affiliations
          [1 ] Graduate Institute of Clinical Medicine, College of Medicine, Taipei Medical University Taipei, Taiwan
          [2 ] Division of Cardiovascular Surgery, Department of Surgery, Wan Fang Hospital, Taipei Medical University Taipei, Taiwan
          [3 ] Department of Medical Education and Research, Wan Fang Hospital, Taipei Medical University Taipei, Taiwan
          [4 ] Division of Cardiovascular Medicine, Department of Internal Medicine, Wan Fang Hospital, Taipei Medical University Taipei, Taiwan
          [5 ] Division of Cardiology, Department of Internal Medicine, School of Medicine, College of Medicine, Taipei Medical University Taipei, Taiwan
          Author notes
          Address correspondence to: Drs. Yi-Jen Chen and Yu-Hsun Kao, Graduate Institute of Clinical Medicine, College of Medicine, Taipei Medical University, 250 Wu-Xing Street, Taipei 11031, Taiwan. Tel: 886-2-27361661 Ext. 3028; E-mail: yjchen@ 123456tmu.edu.tw (YJC); yuhsunkao@ 123456tmu.edu.tw (YHK)
          Article
          PMC6413278 PMC6413278 6413278
          6413278
          30899376
          2b631eee-72a0-4966-952a-279a07e89881
          AJTR Copyright © 2019
          History
          : 20 September 2018
          : 19 December 2018
          Categories
          Original Article

          RUNX2,β-catenin,glycogen synthase kinase 3β,MS-275,Wnt,Calcific aortic valvular disease

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