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Updated: Mar 8, 2026
Isolation and Characterization of Primary Rat Valve Interstitial Cells: A New Model to Study Aortic Valve Calcification
Published on: November 20, 2017
Activated p300 acetyltransferase activity modulates aortic valvular calcification with osteogenic
Shao-Jung Li1, Yu-Hsun Kao2, Cheng-Chih Chung3
1Grarduate Institute of Clinical Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan; Division of Cardiovascular Surgery, Department of Surgery, Wan Fang Hospital, Taipei Medical University, Taipei, Taiwan.
Insights
Histone acetyltransferase (HAT) activity in aortic valve calcification involves osteogenic transdifferentiation. Inhibiting p300 HAT activity may offer a therapeutic strategy for calcific aortic valve disease.
Area of Science:
- Cardiovascular Biology
- Epigenetics
- Molecular Medicine
Background:
- Calcific aortic valve (AV) disease pathogenesis is unclear, lacking optimal pharmacological treatments.
- Histone acetyltransferase (HAT) activity is crucial in osteogenic transdifferentiation and atherosclerosis.
- Investigating HAT's role in AV calcification and therapeutic potential of HAT inhibition is essential.
Purpose of the Study:
- To determine if HAT contributes to AV calcification.
- To assess the therapeutic efficacy of HAT inhibition in AV calcification.
Main Methods:
- Porcine valvular interstitial cells (VICs) were stimulated with osteogenic medium.
- Analyzed myofibroblastic and osteoblastic markers, and effects of p300 inhibitor (C646) on calcification, osteogenesis, HAT activity, MAPK/Akt pathways, and Klotho expression.
Main Results:
- Osteogenic stimulation increased osteocalcin, alkaline phosphatase, and histone H3 acetylation (ac-H3K9).
- C646 inhibited VIC osteogenesis and p300 HAT activity.
- Osteogenic medium decreased Klotho expression, which was restored by C646.
Conclusions:
- Activated p300 HAT activity drives AV calcification via VIC osteogenic transdifferentiation and Klotho modulation.
- p300 inhibition presents a potential therapeutic target for AV calcification.
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 (10ng/mL of tumor necrosis factor-α and 4mmol/L of high phosphate) for 7days. 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, 10μmol/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.
