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Low-level overexpression of p53 promotes warfarin-induced calcification of porcine aortic valve interstitial cells by activating
Low-level overexpression of p53 promotes warfarin-induced calcification of porcine aortic valve interstitial cells by activating
- Source :
- The Journal of biological chemistry. 293(10)
- Publication Year :
- 2017
-
Abstract
- The most frequently used oral anti-coagulant warfarin has been implicated in inducing calcification of aortic valve interstitial cells (AVICs), whereas 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 participates 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. Terminal deoxynucleotidyltransferase-mediated dUTP nick end labeling staining indicated that apoptosis slightly increased in calcific aortic valves than in non-calcific valves. Warfarin treatment led to a low-level increase of p53 mRNA and protein in both 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. shRNA-mediated 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.
- Subjects :
- Male
Sus scrofa
Heart Valve Diseases
Rheumatic Heart Disease
Anticoagulants
Calcinosis
Vitamin K 1
Cell Biology
Antifibrinolytic Agents
Recombinant Proteins
Epigenesis, Genetic
Mice, Inbred C57BL
Disease Models, Animal
Gene Expression Regulation
Genes, Reporter
Aortic Valve
Atrial Fibrillation
Animals
Humans
RNA Interference
Snail Family Transcription Factors
Warfarin
Tumor Suppressor Protein p53
Promoter Regions, Genetic
Cells, Cultured
Subjects
Details
- ISSN :
- 1083351X
- Volume :
- 293
- Issue :
- 10
- Database :
- OpenAIRE
- Journal :
- The Journal of biological chemistry
- Accession number :
- edsair.pmid..........6a202befd5ee0a2f09783cc78e761626