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Updated: Jul 18, 2026
Myocardial Infarction in Neonatal Mice, A Model of Cardiac Regeneration
Published on: May 24, 2016
PUMA is critical for neonatal cardiomyocyte apoptosis induced by endoplasmic reticulum stress
Philip Nickson1, Ambrus Toth, Peter Erhardt
1Boston Biomedical Research Institute, 64 Grove Street, Watertown, MA 02472, USA.
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 muM 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.
Insights
Puma (p53-upregulated modulator of apoptosis) drives ER stress-induced apoptosis in heart cells. Inhibiting Puma may prevent heart failure and treat cardiac infarcts by blocking this cell death pathway.
Area of Science:
- Cardiovascular Biology
- Cell Death Pathways
- Molecular Medicine
Background:
- Puma (p53-upregulated modulator of apoptosis) is a proapoptotic protein involved in diseases like cancer and heart conditions.
- Puma is essential for cardiac cell death following ischemia/reperfusion injury.
- Endoplasmic reticulum (ER) stress is linked to ischemia/reperfusion and cell death.
Purpose of the Study:
- To investigate Puma's role in ER stress-induced cardiomyocyte apoptosis.
- To determine if Puma mediates the apoptotic response to ER stress in heart cells.
Main Methods:
- Primary rat and mouse neonatal cardiomyocytes were treated with ER stress inducers (thapsigargin, tunicamycin).
- Puma expression was reduced using shRNA or gene deletion (knockout mice).
- Apoptosis was measured via TUNEL assay, caspase-3 cleavage, and cytochrome c release.
Main Results:
- ER stress induced Puma expression and apoptosis in rat cardiomyocytes.
- Reducing Puma levels via shRNA or gene deletion conferred resistance to ER stress-induced apoptosis.
- Puma is upregulated transcriptionally during ER stress in cardiac myocytes.
Conclusions:
- Puma is a key mediator of ER stress-induced apoptosis in cardiomyocytes.
- Inhibiting Puma may offer a therapeutic strategy for cardiac infarcts and heart failure by preventing ER stress-mediated cell death.
