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Published on: January 18, 2019
Regulation of PUMA induced by mechanical stress in rat cardiomyocytes
Wen-Pin Cheng1, Gong-Jhe Wu, Bao-Wei Wang
1Department of Medical Education and Research, Shin Kong Wu Ho-Su Memorial Hospital, Taipei, Taiwan.
Background:
PUMA (p53-up-regulated modulator of apoptosis), an apoptosis regulated gene, increased during endoplasmic reticulum stress. However, the expression of PUMA in cardiomyocytes under mechanical stress is little known. We aimed to investigate the regulation mechanism of PUMA expression and apoptosis induced by mechanical stress in cardiomyocytes.
Methods:
Aorta-caval (AV) shunt was performed in adult Wistar rats to induce volume overload. Rat neonatal cardiomyocytes were stretched by vacuum to 20% of maximum elongation at 60 cycles/min.
Results:
PUMA protein and mRNA were up-regulated in the shunt group as compared with sham group. The increased PUMA protein expression and apoptosis induced by shunt was reversed by treatment with atorvastatin at 30 mg/kg/ day orally for 7 days. TUNEL assay showed that treatment with atorvastatin inhibited the apoptosis induced by volume overload. Cyclic stretch significantly enhanced PUMA protein and gene expression. Addition of c-jun N-terminal kinase (JNK) inhibitor SP600125, JNK small interfering RNA (siRNA) and interferon-γ (INF-γ) antibody 30 min before stretch reduced the induction of PUMA protein. Gel shift assay demonstrated that stretch increased the DNA binding activity of interferon regulatory factor-1. Stretch increased, while PUMA-Mut plasmid, SP600125 and INF-γ antibody abolished the PUMA promoter activity induced by stretch. PUMA mediated apoptosis induced by stretch was reversed by PUMA siRNA and atorvastatin.
Conclusions:
Mechanical stress enhanced apoptosis and PUMA expression in cardiomyocytes. Treatment with atorvastatin reversed both PUMA expression and apoptosis induced by mechanical stress in cardiomyocytes.
Insights
Mechanical stress increases cardiomyocyte apoptosis and PUMA expression. Atorvastatin treatment reversed these effects, highlighting its potential therapeutic role in managing cardiac stress-induced cell death.
Area of Science:
- Cardiology
- Molecular Biology
- Cell Biology
Background:
- PUMA (p53-up-regulated modulator of apoptosis) is an apoptosis-regulating gene known to increase during endoplasmic reticulum stress.
- The role of PUMA in cardiomyocytes under mechanical stress remains largely unexplored.
- Investigating PUMA's regulation and its role in mechanical stress-induced cardiomyocyte apoptosis is crucial.
Purpose of the Study:
- To elucidate the regulation mechanism of PUMA expression in cardiomyocytes subjected to mechanical stress.
- To determine the role of PUMA in mechanical stress-induced apoptosis in cardiomyocytes.
- To evaluate the potential protective effects of atorvastatin against mechanical stress-induced cardiomyocyte apoptosis.
Main Methods:
- Aorta-caval (AV) shunt surgery in Wistar rats to induce volume overload.
- In vitro cyclic stretch model applied to rat neonatal cardiomyocytes.
- Western blotting, RT-PCR, TUNEL assay, gel shift assay, and siRNA/inhibitor treatments were employed.
Main Results:
- Mechanical stress (volume overload and cyclic stretch) significantly upregulated PUMA protein and mRNA expression in cardiomyocytes.
- Cyclic stretch-induced PUMA expression was mediated by interferon regulatory factor-1 (IRF-1) activation and c-jun N-terminal kinase (JNK) signaling.
- Atorvastatin treatment (30 mg/kg/day) reversed mechanical stress-induced PUMA upregulation and cardiomyocyte apoptosis.
- PUMA siRNA also reversed stretch-induced apoptosis, confirming PUMA's role in this process.
Conclusions:
- Mechanical stress enhances apoptosis and PUMA expression in cardiomyocytes.
- Atorvastatin effectively reverses mechanical stress-induced PUMA expression and cardiomyocyte apoptosis.
- These findings suggest PUMA as a key mediator of mechanical stress-induced cardiac cell death and atorvastatin as a potential therapeutic agent.
