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Triptolide induces p53-dependent cardiotoxicity through mitochondrial membrane permeabilization in cardiomyocytes
Yue Xi1, Wenwen Wang1, Li Wang1
1School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, PR China.
Toxicology and Applied Pharmacology
|July 17, 2018
Summary
Triptolide causes heart damage by activating the p53 protein, which triggers apoptosis in heart cells. Blocking p53 or its downstream targets prevents this cardiotoxicity.
Area of Science:
- Pharmacology
- Cardiovascular Biology
- Molecular Toxicology
Background:
- Triptolide (TP) is used for inflammatory diseases but causes cardiotoxicity.
- TP inhibits RNA polymerase, causing DNA damage.
- p53 is linked to DNA damage and apoptosis, suggesting its role in TP cardiotoxicity.
Purpose of the Study:
- Investigate the role of p53 in Triptolide-induced cardiotoxicity.
- Elucidate the molecular mechanisms underlying TP-induced heart damage.
Main Methods:
- Utilized cell cultures (H9c2, primary cardiomyocytes) and p53 knockout mice.
- Assessed p53 protein levels, cardiac injury markers (cTn-I), and apoptosis.
- Employed immunoblotting, immunofluorescence, and pharmacological inhibitors (PFTα, BIP V5).
Main Results:
- TP elevated p53 levels in vitro and in vivo.
- p53 deficiency protected against TP-induced heart injury and apoptosis.
- TP-induced cardiotoxicity involved p53 nuclear translocation, Bcl2 family gene regulation, and mitochondrial dysfunction.
- Inhibitors of p53 and Bax ameliorated TP-induced apoptosis.
Conclusions:
- TP-induced cardiotoxicity is mediated by p53 activation.
- The p53-dependent pathway involves mitochondrial outer membrane permeabilization and apoptosis.
- Targeting the p53 pathway may offer therapeutic strategies against Triptolide cardiotoxicity.
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