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Research Article Free access | 10.1172/JCI345

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

X Long, M T Crow, S J Sollott, L O'Neill, D S Menees, M de Lourdes Hipolito, M O Boluyt, T Asai, and E G Lakatta

Laboratory of Cardiovascular Science, Gerontology Research Center, National Institutes of Ageing/National Institutes of Health, Baltimore, Maryland 21224, USA.

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Laboratory of Cardiovascular Science, Gerontology Research Center, National Institutes of Ageing/National Institutes of Health, Baltimore, Maryland 21224, USA.

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Laboratory of Cardiovascular Science, Gerontology Research Center, National Institutes of Ageing/National Institutes of Health, Baltimore, Maryland 21224, USA.

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Laboratory of Cardiovascular Science, Gerontology Research Center, National Institutes of Ageing/National Institutes of Health, Baltimore, Maryland 21224, USA.

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Laboratory of Cardiovascular Science, Gerontology Research Center, National Institutes of Ageing/National Institutes of Health, Baltimore, Maryland 21224, USA.

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Laboratory of Cardiovascular Science, Gerontology Research Center, National Institutes of Ageing/National Institutes of Health, Baltimore, Maryland 21224, USA.

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Laboratory of Cardiovascular Science, Gerontology Research Center, National Institutes of Ageing/National Institutes of Health, Baltimore, Maryland 21224, USA.

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Laboratory of Cardiovascular Science, Gerontology Research Center, National Institutes of Ageing/National Institutes of Health, Baltimore, Maryland 21224, USA.

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Laboratory of Cardiovascular Science, Gerontology Research Center, National Institutes of Ageing/National Institutes of Health, Baltimore, Maryland 21224, USA.

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Published March 15, 1998 - More info

Published in Volume 101, Issue 6 on March 15, 1998
J Clin Invest. 1998;101(6):1453–1461. https://doi.org/10.1172/JCI345.
© 1998 The American Society for Clinical Investigation
Published March 15, 1998 - Version history
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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 A1-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 pHi 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.

Version history
  • Version 1 (March 15, 1998): No description
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