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
N1 - Funding Information:
This study was supported by grants from Taipei Medical University (TMU101-AE1-B54) and Wan Fang Hospital, Taipei Medical University (104swf01, 104-wf-phd-02 and 105-wf-phd-01).
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
M3 - Article
C2 - 28111052
AN - SCOPUS:85009787008
SN - 0167-5273
VL - 232
SP - 271
EP - 279
JO - International Journal of Cardiology
JF - International Journal of Cardiology
ER -