Journal
CARDIOVASCULAR RESEARCH
Volume 73, Issue 1, Pages 48-56Publisher
OXFORD UNIV PRESS
DOI: 10.1016/j.cardiores.2006.10.001
Keywords
myocytes; apoptosis; SR function; signal transduction
Categories
Funding
- NHLBI NIH HHS [R01 HL068126] Funding Source: Medline
- NATIONAL HEART, LUNG, AND BLOOD INSTITUTE [R01HL068126] Funding Source: NIH RePORTER
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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 mu M 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. (c) 2006 European Society of Cardiology. Published by Elsevier B.V. All rights reserved.
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