Non-apoptotic P53 Regulates Aortic Valve Interstitial Cell Calcification

Objective The tumor-suppressor p53 is an important regulator of cell cycle,apoptosis and bone development.The role of p53 in aortic valve interstitial cell(AVIC)calcification remains unknown.In this study,we investigated the role of p53 in the regulation of warfarin induced AVIC calcification.Methods and Results Immunostaining and quantification PCR showed p53 expression was slightly increased in calcific human aortic valves mainly located within AVICs concomitant with slightly increased apoptosis.Low level activation of p53 using adenovirus vector induced increased p300/CBP expression and histone3 acetylation,but not AVIC apoptosis,and promoted warfarin induced AVIC calcium deposition and osteogenic marker genes expression.Knockdown of p53 by short hairpin RNA attenuated AVIC calcium deposition and osteogenic markers expression.Chromatin immunoprecipitation(ChIP)assay and luciferase assay showed p53 was recruited by the promoter of Slug and activated its expression.Knockdown of Slug attenuates AVIC calcification and blocked the p53 mediated AVIC calcium deposition and osteogenic marker genes expression.Conclusions p53 is involved in AVIC calcification and non-apoptotic p53 promotes AVIC calcification via transcrioptionally increasing Slug expression.