Activated p300 acetyltransferase activity modulates aortic valvular calcification with osteogenic transdifferentiation and downregulation of Klotho

研究成果: 雜誌貢獻文章

3 引文 (Scopus)

摘要

Background The calcific aortic valve (AV) disease is a common disease with the unclear mechanism, and optimal pharmacological treatment remains unavailable. Epigenetic modulation by histone acetyltransferase (HAT) plays a critical role in osteogenic transdifferentiation and atherosclerosis. The purposes of this study were to investigate whether HAT contributes to the pathophysiology of AV calcification and assess the therapeutic potential of HAT inhibition. Methods Porcine valvular interstitial cells (VICs) were treated with osteogenic medium (10 ng/mL of tumor necrosis factor-α and 4 mmol/L of high phosphate) for 7 days. We analyzed the RNA and protein expression of myofibroblastic (α-SMA, vimentin, collagen 1A1, collagen 3, Egr-1, MMP2, MMP9) and osteoblastic markers (osteocalcin and alkaline phosphatase) in VICs, and studied the effects of a p300 inhibitor (C646, 10 μmol/L) on calcification (Alizarin Red S staining), osteogenesis, HAT activity, the mitogen-activated protein kinase (MAPK) and Akt pathway, and Klotho expression on VICs. Results Osteogenic medium treated VICs had higher expressions of osteocalcin, alkaline phosphatase and acetylated lysine-9 of histone H3 (ac-H3K9) than control cells. C646 attenuated osteogenesis of VICs with simultaneous inhibition of the HAT activity of p300. There was neither significant increase of p300 protein nor p300 transcript during the osteogenesis process. Additionally, osteogenic medium treated VICs decreased the expression of Klotho, which is attenuated by C646. Conclusions Activated HAT activity of p300 modulates AV calcification through osteogenic transdifferentiation of VICs with Klotho modulation. P300 inhibition is a potential therapeutic target for AV calcification.
原文英語
頁(從 - 到)271-279
頁數9
期刊International Journal of Cardiology
232
DOIs
出版狀態已發佈 - 四月 1 2017

指紋

Histone Acetyltransferases
Down-Regulation
Osteogenesis
Osteocalcin
Alkaline Phosphatase
Collagen
Aortic Diseases
p300-CBP-associated factor
Vimentin
Mitogen-Activated Protein Kinases
Aortic Valve
Epigenomics
Histones
Lysine
Atherosclerosis
Proteins
Swine
Tumor Necrosis Factor-alpha
Phosphates
Pharmacology

ASJC Scopus subject areas

  • Medicine(all)
  • Cardiology and Cardiovascular Medicine

引用此文

@article{77204cf1bec24f94899edeca7f0789bf,
title = "Activated p300 acetyltransferase activity modulates aortic valvular calcification with osteogenic transdifferentiation and downregulation of Klotho",
abstract = "Background The calcific aortic valve (AV) disease is a common disease with the unclear mechanism, and optimal pharmacological treatment remains unavailable. Epigenetic modulation by histone acetyltransferase (HAT) plays a critical role in osteogenic transdifferentiation and atherosclerosis. The purposes of this study were to investigate whether HAT contributes to the pathophysiology of AV calcification and assess the therapeutic potential of HAT inhibition. Methods Porcine valvular interstitial cells (VICs) were treated with osteogenic medium (10 ng/mL of tumor necrosis factor-α and 4 mmol/L of high phosphate) for 7 days. We analyzed the RNA and protein expression of myofibroblastic (α-SMA, vimentin, collagen 1A1, collagen 3, Egr-1, MMP2, MMP9) and osteoblastic markers (osteocalcin and alkaline phosphatase) in VICs, and studied the effects of a p300 inhibitor (C646, 10 μmol/L) on calcification (Alizarin Red S staining), osteogenesis, HAT activity, the mitogen-activated protein kinase (MAPK) and Akt pathway, and Klotho expression on VICs. Results Osteogenic medium treated VICs had higher expressions of osteocalcin, alkaline phosphatase and acetylated lysine-9 of histone H3 (ac-H3K9) than control cells. C646 attenuated osteogenesis of VICs with simultaneous inhibition of the HAT activity of p300. There was neither significant increase of p300 protein nor p300 transcript during the osteogenesis process. Additionally, osteogenic medium treated VICs decreased the expression of Klotho, which is attenuated by C646. Conclusions Activated HAT activity of p300 modulates AV calcification through osteogenic transdifferentiation of VICs with Klotho modulation. P300 inhibition is a potential therapeutic target for AV calcification.",
keywords = "Aortic valve calcification, Klotho, Osteogenesis, P300, Valvular interstitial cells",
author = "Li, {Shao Jung} and Kao, {Yu Hsun} and Chung, {Cheng Chih} and Chen, {Wei Yu} and Cheng, {Wan Li} and Chen, {Yi Jen}",
year = "2017",
month = "4",
day = "1",
doi = "10.1016/j.ijcard.2017.01.005",
language = "English",
volume = "232",
pages = "271--279",
journal = "International Journal of Cardiology",
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TY - JOUR

T1 - Activated p300 acetyltransferase activity modulates aortic valvular calcification with osteogenic transdifferentiation and downregulation of Klotho

AU - Li, Shao Jung

AU - Kao, Yu Hsun

AU - Chung, Cheng Chih

AU - Chen, Wei Yu

AU - Cheng, Wan Li

AU - Chen, Yi Jen

PY - 2017/4/1

Y1 - 2017/4/1

N2 - Background The calcific aortic valve (AV) disease is a common disease with the unclear mechanism, and optimal pharmacological treatment remains unavailable. Epigenetic modulation by histone acetyltransferase (HAT) plays a critical role in osteogenic transdifferentiation and atherosclerosis. The purposes of this study were to investigate whether HAT contributes to the pathophysiology of AV calcification and assess the therapeutic potential of HAT inhibition. Methods Porcine valvular interstitial cells (VICs) were treated with osteogenic medium (10 ng/mL of tumor necrosis factor-α and 4 mmol/L of high phosphate) for 7 days. We analyzed the RNA and protein expression of myofibroblastic (α-SMA, vimentin, collagen 1A1, collagen 3, Egr-1, MMP2, MMP9) and osteoblastic markers (osteocalcin and alkaline phosphatase) in VICs, and studied the effects of a p300 inhibitor (C646, 10 μmol/L) on calcification (Alizarin Red S staining), osteogenesis, HAT activity, the mitogen-activated protein kinase (MAPK) and Akt pathway, and Klotho expression on VICs. Results Osteogenic medium treated VICs had higher expressions of osteocalcin, alkaline phosphatase and acetylated lysine-9 of histone H3 (ac-H3K9) than control cells. C646 attenuated osteogenesis of VICs with simultaneous inhibition of the HAT activity of p300. There was neither significant increase of p300 protein nor p300 transcript during the osteogenesis process. Additionally, osteogenic medium treated VICs decreased the expression of Klotho, which is attenuated by C646. Conclusions Activated HAT activity of p300 modulates AV calcification through osteogenic transdifferentiation of VICs with Klotho modulation. P300 inhibition is a potential therapeutic target for AV calcification.

AB - Background The calcific aortic valve (AV) disease is a common disease with the unclear mechanism, and optimal pharmacological treatment remains unavailable. Epigenetic modulation by histone acetyltransferase (HAT) plays a critical role in osteogenic transdifferentiation and atherosclerosis. The purposes of this study were to investigate whether HAT contributes to the pathophysiology of AV calcification and assess the therapeutic potential of HAT inhibition. Methods Porcine valvular interstitial cells (VICs) were treated with osteogenic medium (10 ng/mL of tumor necrosis factor-α and 4 mmol/L of high phosphate) for 7 days. We analyzed the RNA and protein expression of myofibroblastic (α-SMA, vimentin, collagen 1A1, collagen 3, Egr-1, MMP2, MMP9) and osteoblastic markers (osteocalcin and alkaline phosphatase) in VICs, and studied the effects of a p300 inhibitor (C646, 10 μmol/L) on calcification (Alizarin Red S staining), osteogenesis, HAT activity, the mitogen-activated protein kinase (MAPK) and Akt pathway, and Klotho expression on VICs. Results Osteogenic medium treated VICs had higher expressions of osteocalcin, alkaline phosphatase and acetylated lysine-9 of histone H3 (ac-H3K9) than control cells. C646 attenuated osteogenesis of VICs with simultaneous inhibition of the HAT activity of p300. There was neither significant increase of p300 protein nor p300 transcript during the osteogenesis process. Additionally, osteogenic medium treated VICs decreased the expression of Klotho, which is attenuated by C646. Conclusions Activated HAT activity of p300 modulates AV calcification through osteogenic transdifferentiation of VICs with Klotho modulation. P300 inhibition is a potential therapeutic target for AV calcification.

KW - Aortic valve calcification

KW - Klotho

KW - Osteogenesis

KW - P300

KW - Valvular interstitial cells

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U2 - 10.1016/j.ijcard.2017.01.005

DO - 10.1016/j.ijcard.2017.01.005

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JO - International Journal of Cardiology

JF - International Journal of Cardiology

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