Inhibition of acetylation of histones 3 and 4 attenuates aortic valve calcification

Jia Gu, Yan Lu, Menqing Deng, Ming Qiu, Yunfan Tian, Yue Ji, Pengyu Zong, Yongfeng Shao, Rui Zheng, Bin Zhou, Wei Sun, Xiangqing Kong

Research output: Contribution to journalArticle

Abstract

Aortic valve calcification develops in patients with chronic kidney disease who have calcium and phosphate metabolic disorders and poor prognoses. There is no effective treatment except valve replacement. However, metabolic disorders put patients at high risk for surgery. Increased acetylation of histones 3 and 4 is present in interstitial cells from human calcific aortic valves, but whether it is involved in aortic valve calcification has not been studied. In this study, we found that treating cultured porcine aortic valve interstitial cells with a high-calcium/high-phosphate medium induced calcium deposition, apoptosis, and expression of osteogenic marker genes, producing a phenotype resembling valve calcification in vivo. These phenotypic changes were attenuated by the histone acetyltransferase inhibitor C646. C646 treatment increased the levels of class I histone deacetylase members and decreased the acetylation of histones 3 and 4 induced by the high-calcium/high-phosphate treatment. Conversely, the histone deacetylase inhibitor suberoylanilide hydroxamic acid promoted valve interstitial cell calcification. In a mouse model of aortic valve calcification induced by adenine and vitamin D treatment, the levels of acetylated histones 3 and 4 were increased in the calcified aortic valves. Treatment of the models with C646 attenuated aortic valve calcification by restoring the levels of acetylated histones 3 and 4. These observations suggest that increased acetylation of histones 3 and 4 is part of the pathogenesis of aortic valve calcification associated with calcium and phosphate metabolic disorders. Targeting acetylated histones 3 and 4 may be a potential therapy for inoperable aortic valve calcification in chronic kidney disease patients.

Original languageEnglish (US)
Article number79
JournalExperimental and Molecular Medicine
Volume51
Issue number7
DOIs
StatePublished - Jul 1 2019

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Acetylation
Histones
Aortic Valve
Calcium
Chronic Renal Insufficiency
Therapeutics
Phosphates
Histone Acetyltransferases
Histone Deacetylase Inhibitors
Histone Deacetylases
Adenine
Vitamin D
Surgery
Calcification of Aortic Valve
Swine
Genes
Apoptosis
Phenotype
calcium phosphate

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Medicine
  • Molecular Biology
  • Clinical Biochemistry

Cite this

Inhibition of acetylation of histones 3 and 4 attenuates aortic valve calcification. / Gu, Jia; Lu, Yan; Deng, Menqing; Qiu, Ming; Tian, Yunfan; Ji, Yue; Zong, Pengyu; Shao, Yongfeng; Zheng, Rui; Zhou, Bin; Sun, Wei; Kong, Xiangqing.

In: Experimental and Molecular Medicine, Vol. 51, No. 7, 79, 01.07.2019.

Research output: Contribution to journalArticle

Gu, J, Lu, Y, Deng, M, Qiu, M, Tian, Y, Ji, Y, Zong, P, Shao, Y, Zheng, R, Zhou, B, Sun, W & Kong, X 2019, 'Inhibition of acetylation of histones 3 and 4 attenuates aortic valve calcification', Experimental and Molecular Medicine, vol. 51, no. 7, 79. https://doi.org/10.1038/s12276-019-0272-9
Gu, Jia ; Lu, Yan ; Deng, Menqing ; Qiu, Ming ; Tian, Yunfan ; Ji, Yue ; Zong, Pengyu ; Shao, Yongfeng ; Zheng, Rui ; Zhou, Bin ; Sun, Wei ; Kong, Xiangqing. / Inhibition of acetylation of histones 3 and 4 attenuates aortic valve calcification. In: Experimental and Molecular Medicine. 2019 ; Vol. 51, No. 7.
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