Enhanced expression of p53 and apoptosis induced by blockade of the vacuolar proton ATPase in cardiomyocytes

Xilin Long, Michael T. Crow, Steven J. Sollott, Lydia O'Neill, Daniel S. Menees, Maria De Lourdes Hipolito, Marvin O. Boluyt, Toshinobu Asai, Edward G. Lakatta

Research output: Contribution to journalArticle

Abstract

Activation of the vacuolar proton ATPase (VPATPase) has been implicated in the prevention of apoptosis in neutrophils and adult cardiac myocytes. To determine the role of the VPATPase in apoptosis of cardiac myocytes, we used a potent and specific inhibitor of the VPATPase, bafilomycin A1. Bafilomycin A1 alone caused increased DNA laddering of genomic DNA and increased nuclear staining for fragmented DNA in neonatal cardiomyocyte apoptosis in a dose- and time-dependent manner. Intracellular acidification in cardiac myocytes was also observed after 18 h of bafilomycin A1 treatment. Accordingly, bafilomycin Al-treated myocytes also showed increased accumulation of p53 protein and p53-dependent transactivation of gene expression, including a persistent upregulation of p21/wild-type p53 activated fragment 1/cyclin kinase inhibitor protein-1 mRNA. The bafilomycin A1-induced increase in p53 protein levels was accompanied by a marked increase in p53 mRNA accumulation. In contrast, cardiac fibroblasts treated with bafilomycin A1 showed no change in p53 protein expression or pH(i) and did not undergo apoptosis even after 24 h of treatment. Our data suggest that blockade of the VPATPase induces apoptotic cell death of cardiac myocytes and that this may occur through a p53-mediated apoptotic pathway.

Original languageEnglish (US)
Pages (from-to)1453-1461
Number of pages9
JournalJournal of Clinical Investigation
Volume101
Issue number6
DOIs
StatePublished - Mar 15 1998

Keywords

  • Apoptosis
  • Bafilomycin A1
  • Cardiac myocyte
  • Vacuolar proton ATPase

ASJC Scopus subject areas

  • Medicine(all)

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    Long, X., Crow, M. T., Sollott, S. J., O'Neill, L., Menees, D. S., Hipolito, M. D. L., Boluyt, M. O., Asai, T., & Lakatta, E. G. (1998). Enhanced expression of p53 and apoptosis induced by blockade of the vacuolar proton ATPase in cardiomyocytes. Journal of Clinical Investigation, 101(6), 1453-1461. https://doi.org/10.1172/JCI345