p53 and the hypoxia-induced apoptosis of cultured neonatal rat cardiac myocytes

Xilin Long, Marvin O. Boluyt, Maria De Lourdes Hipolito, Martha S. Lundberg, Jing Sheng Zheng, Lydia O'Neill, Corrado Cirielli, Edward G. Lakatta, Michael T. Crow

Research output: Contribution to journalArticle

Abstract

Myocyte cell loss is a prominent and important pathogenic feature of cardiac ischemia. We have used cultured neonatal rat cardiac myocytes exposed to prolonged hypoxia as an experimental system to identify critical factors involved in cardiomyocyte death. Exposure of myocytes to hypoxia for 48 h resulted in intranucleosomal cleavage of genomic DNA characteristic of apoptosis and was accompanied by increased p53 transactivating activity and protein accumulation. Expression of p21/WAF-1/CIP-1, a well-characterized target of p53 transactivation, also increased in response to hypoxia. Hypoxia did not cause DNA laddering or cell loss in cardiac fibroblasts. To determine whether the increase in p53 expression in myocytes was sufficient to induce apoptosis, normoxic cultures were infected with a replication-defective adenovirus expressing wild-type human p53 (AdCMV.p53). Infected cells expressed high intracellular levels of p53 protein and exhibited the morphological changes and genomic DNA fragmentation characteristic of apoptosis. In contrast, no genomic DNA fragmentation was observed in myocytes infected with the control virus lacking an insert (AdCMV.null) or in cardiac fibroblasts infected with AdCMV.p53. These results suggest that the intracellular signaling pathways activated by p53 might play a critical role in the regulation of hypoxia-induced apoptosis of cardiomyocytes.

Original languageEnglish (US)
Pages (from-to)2635-2643
Number of pages9
JournalJournal of Clinical Investigation
Volume99
Issue number11
DOIs
StatePublished - Jun 1 1997

Keywords

  • Apoptosis
  • Cardiomyocytes
  • Hypoxia
  • Ischemia
  • P53

ASJC Scopus subject areas

  • Medicine(all)

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    Long, X., Boluyt, M. O., De Lourdes Hipolito, M., Lundberg, M. S., Zheng, J. S., O'Neill, L., Cirielli, C., Lakatta, E. G., & Crow, M. T. (1997). p53 and the hypoxia-induced apoptosis of cultured neonatal rat cardiac myocytes. Journal of Clinical Investigation, 99(11), 2635-2643. https://doi.org/10.1172/JCI119452