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

Li, Shao Jung; Kao, Yu Hsun; Chung, Cheng Chih; Chen, Wei Yu; Cheng, Wanli; Chen, Yi Jen

doi:10.1016/j.ijcard.2017.01.005

Cited by 20 publications

(23 citation statements)

References 48 publications

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“…In the current study, we found that p53 not only promoted Slug transcription, but also increased the levels of histone acetyltransferases p300 and CBP, and resulted in increased histone H3 and H4 acetylation. These epigenetic changes have been reported to regulate the terminal differentiation of osteoblastic progenitor cells and calcification of pAVICs (17)(18)(19)36). We suggest that p53 induced Slug expression initiates osteoblastic transdifferentiation at the early stage, and the epigenetic changes may contribute to the calcium deposition at the late stage of pAVIC calcification.…”

Section: Discussionmentioning

confidence: 54%

“…5G, H). p53 promotes pAVIC calcification by increasing slug transcription Since epigenetic changes of histone acetylation and associated histone acetyltransferase p300 and CREB-binding protein (CBP) have been reported promoting osteoblastic maturation and AVIC calcification (17)(18)(19). To dissect the mechanism of p53-regulated pAVIC calcification, we analyzed the epigenetic changes induced by p53.…”

Section: Knockdown Of P53 Attenuates Warfarin-induced Pavic Calcificamentioning

confidence: 99%

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Low-level overexpression of p53 promotes warfarin-induced calcification of porcine aortic valve interstitial cells by activating Slug gene transcription

Gao¹,

Ji²,

Lü³

et al. 2018

Journal of Biological Chemistry

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The most frequently used oral anti-coagulant warfarin has been implicated in inducing calcification of aortic valve interstitial cells (AVICs), while the mechanism is not fully understood. The low-level activation of p53 is found to be involved in osteogenic transdifferentiation and calcification of AVICs. Whether p53 participating in warfarin-induced AVIC calcification remains unknown. In this study, we investigated the role of low-level p53 overexpression in warfarin-induced porcine AVIC (pAVIC) calcification.Immunostaining, quantitative PCR and western blotting revealed that p53 was expressed in human and pAVICs and that p53 expression was slightly increased in calcific human aortic valves compared with non-calcific valves. TUNEL staining indicated that apoptosis slightly increased in calcific aortic valves than in non-calcific valves. Warfarin treatment led to lowlevel increase of p53 mRNA and protein both in pAVICs and mouse aortic valves. Low-level overexpression of p53 in pAVICs via an adenovirus vector did not affect pAVIC apoptosis, but promoted warfarin-induced calcium deposition and expression of osteogenic markers. shRNAmediated p53 knockdown attenuated the pAVIC calcium deposition and osteogenic marker expression. Moreover, ChIP and luciferase assays showed that p53 was recruited to the slug promoter and activated slug expression in calcific pAVICs. Of note, overexpression of Slug increased osteogenic marker Runx2 expression, but not pAVIC calcium deposition, and Slug knockdown attenuated pAVIC calcification and p53-mediated pAVIC calcium deposition and expression of osteogenic markers. In conclusion, we found that p53 plays an important role in warfarin induced pAVIC calcification and increased slug transcription by p53 is required for p53-mediated pAVIC calcification.The tumor suppressor p53 plays important roles in cell cycle regulation, apoptosis, and DNA p53 and aortic valve interstitial cell calcification 2 damage (1), as well as in osteoblastic differentiation and bone development. Deletion of the p53 inhibitor MDM2 in osteoblast lineage cells leads to increased p53 production and suppression of bone organogenesis and homeostasis, whereas deletion of p53 accelerates osteoblast cell differentiation and bone formation (2,3). In addition, using p53 knockout mice with chronic kidney disease, Li, KL, et al. showed that p53 negatively regulates osteogenic differentiation of vascular smooth muscle cells and aortic calcification suggesting the p53 is involved in pathological tissue calcification (4).The vitamin K antagonist, warfarin, is the most frequently used oral anti-coagulant to treat thromboprophylaxis in the presence of atrial fibrillation or a mechanical prosthetic heart valve. Recently, human and animal studies have implicated warfarin use with vascular and valvular calcification. Long-term warfarin treatment impairs vitamin K-dependent modification of many proteins, including matrix gla protein (MGP), inhibits the bone morphogenetic protein 2 (BMP2) and bone morphogenetic protein...

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Section: Discussionmentioning

confidence: 54%

Section: Knockdown Of P53 Attenuates Warfarin-induced Pavic Calcificamentioning

confidence: 99%

Low-level overexpression of p53 promotes warfarin-induced calcification of porcine aortic valve interstitial cells by activating Slug gene transcription

Gao¹,

Ji²,

Lü³

et al. 2018

Journal of Biological Chemistry

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“…As known, HP is capable of inducing epigenetic modifications, including DNA methylation and histone acetylation 23,39 , which mediate the effects of HP, such as fibrotic fibroblast activation and osteogenic transdifferentiation 39,40 . As cardiac hypertrophy and HF could be rescued by inhibition of DNA methylation or histone acetylation 41,42 , methylation and acetylation may also have important roles in the pathogenesis of cardiac hypertrophy.…”

Section: Discussionmentioning

confidence: 99%

IRF1-mediated downregulation of PGC1α contributes to cardiorenal syndrome type 4

et al. 2020

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Cardiorenal syndrome type 4 (CRS4) is a common complication of chronic kidney disease (CKD), but the pathogenic mechanisms remain elusive. Here we report that morphological and functional changes in myocardial mitochondria are observed in CKD mice, especially decreases in oxidative phosphorylation and fatty acid metabolism. High phosphate (HP), a hallmark of CKD, contributes to myocardial energy metabolism dysfunction by downregulating peroxisome proliferator-activated receptor gamma coactivator 1 alpha (PGC1α). Furthermore, the transcriptional factor interferon regulatory factor 1 (IRF1) is revealed as the key molecule upregulated by HP through histone H3K9 acetylation, and responsible for the HP-mediated transcriptional inhibition of PGC1α by directly binding to its promoter region. Conversely, restoration of PGC1α expression or genetic knockdown of IRF1 significantly attenuates HP-induced alterations in vitro and in vivo. These findings demonstrate that IRF1-PGC1α axis-mediated myocardial energy metabolism remodeling plays a crucial role in the pathogenesis of CRS4.

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“…Therefore, the aberrant expression of CREBBP may have impact on calcification which is consistent with the results of the present study. Furthermore, it was reported that the translocation of CiTED1 is enhanced by the protein kinase C activator (27,28). a number of studies have set out to determine the role of mir-330-3p in different types of tumors, most of which have reported mir-330-3p-3p as a tumor suppressor gene.…”

Section: Discussionmentioning

confidence: 99%

“…a number of classic alteration patterns are involved in calcification, including receptor translocation mediated by serine mutation and epigenetic modulation regulated by histone acetyltransferase (19,26). Previous studies reported the association between creBBP and aortic calcification, and suggested that CREBBP ultimately promotes calcification via its translocation from the cytoplasm to the nucleus (27). Taken together, the results of the present study and findings from previous studies indicated that the alteration of creBBP via mir-330-3p might aggravate susceptibility toward early calcification observed in patients with BAV.…”

Section: Discussionmentioning

confidence: 99%

Upregulated microRNA‑330‑3p promotes calcification in the bicuspid aortic valve via targeting CREBBP

Zheng

Líu

et al. 2020

Mol Med Rep

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one key risk factor of aortic valve stenosis in clinical practice is bicuspid aortic valve (BaV). increasing evidence indicates that numerous micrornas (mirs/mirnas) are involved in BaV calcification via their target genes. mir-330-3p was found to be involved in the deterioration of BAV calcification by miR profiling in human calcified BAV and tricuspid aortic valve (TAV) tissues in the present study and the underlying mechanism was investigated. rna sequencing was performed on four BaV and four TaV tissues from patients with aortic stenosis before these leaflets were examined for the expression levels of mir-330-3p and creB-binding protein (creBBP) by reverse transcription-Pcr. The alteration of functional factors associated with calcification was also assessed by Western blotting and immunohistochemistry in human aortic tissue samples. The putative target of mir-330-3p was detected by dual-luciferase assay in 293 cells. Furthermore, the influence of miR-330-3p expression on osteogenic progression was explored in cultured porcine valve interstitial cells (VICs). Rescue experiments of CRBBP were performed to confirm the influence of the miR-330-3p-CREBBP pathway in the calcification progress in porcine Vics. rna sequencing indicated distinct expression of miR-330-3p in human BAV tissues compared with TAV, which was then confirmed by PCR. CREBBP expression levels in human BAV and TAV leaflets also demonstrated the opposite alterations. This negative correlation was then confirmed in cultured porcine VICs. Under an osteogenic environment, cellular calcification was promoted in miR-330-3p-overexpressed porcine VICs expressing higher bone morphogenetic protein 2, Runt-related transcription factor 2, matrix metalloproteinase (MMP)-2, MMP-9 and collagen i compared with controls. rescue experiments further confirmed that miR-330-3p played its role via targeting creBBP in porcine Vics. collectively, miR-330-3p was upregulated in calcified BAV compared with TAV. The upregulation of miR-330-3p promotes the calcification progress partially via targeting creBBP.

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

Cited by 20 publications

References 48 publications

Low-level overexpression of p53 promotes warfarin-induced calcification of porcine aortic valve interstitial cells by activating Slug gene transcription

Low-level overexpression of p53 promotes warfarin-induced calcification of porcine aortic valve interstitial cells by activating Slug gene transcription

IRF1-mediated downregulation of PGC1α contributes to cardiorenal syndrome type 4

Upregulated microRNA‑330‑3p promotes calcification in the bicuspid aortic valve via targeting CREBBP

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