PUMA is critical for neonatal cardiomyocyte apoptosis induced by endoplasmic reticulum stress

Philip Nickson, A. Tóth, Peter Erhardt

Research output: Contribution to journalArticle

113 Citations (Scopus)

Abstract

Objective: Puma (p53-upregulated modulator of apoptosis), a proapoptotic BH3-only member of the Bcl-2 protein family, has been implicated in the pathomechanism of several diseases, including cancer, AIDS, and ischemic brain disease. We have recently shown that Puma is required for cardiac cell death upon ischemia/reperfusion of mouse hearts. Since ischemia/reperfusion is also associated with endoplasmic reticulum (ER) stress, in the present study we investigated whether Puma contributes to the ER stress-dependent component of cardiomyocyte apoptosis. Methods: Primary cultures of rat and mouse neonatal cardiomyocytes were treated with 3 μM thapsigargin or 100 ng mL- 1 tunicamycin. Puma levels were suppressed by adenoviral delivery of shRNA or targeted deletion of the puma gene. Puma expression was detected by RT-PCR and Western blotting. Apoptosis was assessed by TUNEL assay, caspase-3 cleavage, and cytochrome c release. Results: We have shown that in rat neonatal cardiac myocytes, thapsigargin or tunicamycin treatment led to ER-stress, transcriptional upregulation of Puma, and apoptosis. Most importantly, cardiac myocytes acquired resistance to ER stress-induced apoptosis if Puma expression was downregulated by adenoviral delivery of shRNA or eliminated by targeted deletion in knockout mice. Conclusion: Taken together, our data indicate that Puma is a critical component of ER stress-induced apoptosis in cardiac myocytes, and inhibition of Puma activity may be used to treat cardiac infarcts or prevent heart failure by blocking ER stress-induced apoptosis.

Original languageEnglish
Pages (from-to)48-56
Number of pages9
JournalCardiovascular Research
Volume73
Issue number1
DOIs
Publication statusPublished - Jan 1 2007

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Endoplasmic Reticulum Stress
Cardiac Myocytes
Apoptosis
Tunicamycin
Thapsigargin
Small Interfering RNA
Reperfusion
Ischemia
Puma
Gene Deletion
In Situ Nick-End Labeling
Brain Diseases
Cytochromes c
Knockout Mice
Caspase 3

Keywords

  • Apoptosis
  • Myocytes
  • Signal transduction
  • SR function

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine

Cite this

PUMA is critical for neonatal cardiomyocyte apoptosis induced by endoplasmic reticulum stress. / Nickson, Philip; Tóth, A.; Erhardt, Peter.

In: Cardiovascular Research, Vol. 73, No. 1, 01.01.2007, p. 48-56.

Research output: Contribution to journalArticle

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