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Cardioprotection against myocardial infarction with PTD-BIR3/RING, a XIAP mimicking protein
Richard Souktani1, Sandrine Pons, Christelle Guegan
1Plateforme Petit Animal, INSERM U 955, Créteil, F-94010, France.
Abstract:
The purpose of the present study was to investigate the potential cardioprotective effects of an original approach based on the properties of the X chromosome-linked Inhibitor of Apoptosis (XIAP), the most effective endogenous inhibitor of apoptosis. For this purpose, the C-terminal part of XIAP (BIR3 and RING domains) was fused to the protein transduction domain (PTD) of the HIV1 transactivator of transcription, which confers to fused protein the ability to cross cell membranes. This protein, so-called PTD-BIR3/RING, was administered intravenously in C57BL/6J mice subjected to 30 min coronary artery occlusion and 24 h of reperfusion. Administration of PTD-BIR3/RING at 5 min before and 30 min after the onset of reperfusion reduced infarct size vs control (23+/-2% vs 41+/-4% and 27+/-4% vs 41+/-3%, respectively, p<0.05). Similar reduction in infarct size was observed when PTD-BIR3/RING was administered prior to ischemia (28+/-1% vs 44+/-3%). In addition to inhibition of caspase-3 and -9 activities, PTD-BIR3/RING induced an inhibition of caspase-8 and several other actors of the apoptotic pathways. In conclusion, this study demonstrates that the administration of PTD-BIR3/RING reduces myocardial infarct size even when injected during reperfusion through interruption of caspase activation by pharmacologically mimicking endogenous XIAP.
Insights
This study shows that PTD-BIR3/RING, a novel protein, effectively reduces heart attack size in mice. Administering this X chromosome-linked Inhibitor of Apoptosis (XIAP) mimetic during reperfusion protects the heart by inhibiting apoptosis.
Area of Science:
- Cardiovascular Science
- Molecular Biology
- Apoptosis Research
Background:
- Ischemic heart disease remains a leading cause of mortality worldwide.
- Apoptosis, or programmed cell death, plays a critical role in myocardial injury during ischemia-reperfusion.
- The X chromosome-linked Inhibitor of Apoptosis (XIAP) is a potent endogenous inhibitor of apoptosis.
Purpose of the Study:
- To investigate the cardioprotective potential of a novel engineered protein mimicking XIAP.
- To evaluate the efficacy of PTD-BIR3/RING in reducing myocardial infarct size in a mouse model of cardiac ischemia-reperfusion.
- To elucidate the mechanism of action of PTD-BIR3/RING in inhibiting apoptotic pathways.
Main Methods:
- Construction of a fusion protein, PTD-BIR3/RING, by combining the XIAP BIR3/RING domains with a protein transduction domain (PTD).
- Intravenous administration of PTD-BIR3/RING in C57BL/6J mice subjected to 30 minutes of coronary artery occlusion and 24 hours of reperfusion.
- Assessment of infarct size and analysis of caspase activities (caspase-3, -9, -8) to evaluate apoptotic pathway inhibition.
Main Results:
- PTD-BIR3/RING administration significantly reduced myocardial infarct size when given before reperfusion or even after reperfusion onset.
- Pre-ischemic administration of PTD-BIR3/RING also demonstrated a significant reduction in infarct size.
- The treatment effectively inhibited the activity of key apoptotic executioners, including caspase-3, -9, and -8.
Conclusions:
- The engineered protein PTD-BIR3/RING exhibits significant cardioprotective effects against ischemia-reperfusion injury.
- Pharmacological mimicry of endogenous XIAP via PTD-BIR3/RING can effectively reduce myocardial infarct size.
- This approach offers a promising therapeutic strategy for treating ischemic heart disease by interrupting apoptotic signaling pathways.