Hdac i inhibitor regulates runx2 transactivation through canonical and non-canonical wnt signaling in aortic valvular interstitial cells

研究成果: 雜誌貢獻文章

摘要

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.
原文英語
文章編號AJTR0089749
頁(從 - 到)744-754
頁數11
期刊American Journal of Translational Research
11
發行號2
出版狀態已發佈 - 一月 1 2019

指紋

Histone Deacetylases
Transcriptional Activation
Glycogen Synthase Kinase 3
Bone Morphogenetic Proteins
Catenins
Aortic Diseases
Wnt Signaling Pathway
Osteocalcin
Acetylation
Aortic Valve
Osteogenesis
Histones
Alkaline Phosphatase
Real-Time Polymerase Chain Reaction
Polymerase chain reaction
Protein Isoforms
Cell proliferation
Transcription Factors
Swine
Down-Regulation

ASJC Scopus subject areas

  • Molecular Medicine
  • Clinical Biochemistry
  • Cancer Research

引用此文

@article{547ca2dc146c4a8e9341717476ebf45b,
title = "Hdac i inhibitor regulates runx2 transactivation through canonical and non-canonical wnt signaling in aortic valvular interstitial cells",
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.",
keywords = "Calcific aortic valvular disease, Glycogen synthase kinase 3β, MS-275, RUNX2, Wnt, β-catenin",
author = "Li, {Shao Jung} and Kao, {Yu Hsun} and Chung, {Cheng Chih} and Cheng, {Wan Li} and Chen, {Yi Jen}",
year = "2019",
month = "1",
day = "1",
language = "English",
volume = "11",
pages = "744--754",
journal = "American Journal of Translational Research",
issn = "1943-8141",
publisher = "e-Century Publishing Corporation",
number = "2",

}

TY - JOUR

T1 - Hdac i inhibitor regulates runx2 transactivation through canonical and non-canonical wnt signaling in aortic valvular interstitial cells

AU - Li, Shao Jung

AU - Kao, Yu Hsun

AU - Chung, Cheng Chih

AU - Cheng, Wan Li

AU - Chen, Yi Jen

PY - 2019/1/1

Y1 - 2019/1/1

N2 - 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.

AB - 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.

KW - Calcific aortic valvular disease

KW - Glycogen synthase kinase 3β

KW - MS-275

KW - RUNX2

KW - Wnt

KW - β-catenin

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M3 - Article

AN - SCOPUS:85063474551

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JO - American Journal of Translational Research

JF - American Journal of Translational Research

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