Journal
CARDIOVASCULAR RESEARCH
Volume 116, Issue 3, Pages 633-644Publisher
OXFORD UNIV PRESS
DOI: 10.1093/cvr/cvz145
Keywords
Cardioprotection; Apoptosis; Reperfusion Injury; Therapeutic peptide; DAXX
Categories
Funding
- Agence Nationale pour la Recherche [ANR-08-Genopat-031, ANR-12-EMMA-0009]
- Fondation pour la Recherche Medicale (FRM)
- `Fonds Europeen de Developpement Regional' [FEDER] [43457]
- Region Languedoc-Roussillon
- CNRS-SERVIER [098976]
- SATT AxLR [099482]
- Eurobiodev [099483]
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Aims Regulated cell death is a main contributor of myocardial ischaemia-reperfusion (IR) injury during acute myocardial infarction. In this context, targeting apoptosis could be a potent therapeutical strategy. In a previous study, we showed that DAXX (death-associated protein) was essential for transducing the FAS-dependent apoptotic signal during IR injury. The present study aims at evaluating the cardioprotective effects of a synthetic peptide inhibiting FAS:DAXX interaction. Methods and results An interfering peptide was engineered and then coupled to the Tat cell penetrating peptide (Tat-DAXXp). Its internalization and anti-apoptotic properties were demonstrated in primary cardiomyocytes. Importantly, an intravenous bolus injection of Tat-DAXXp (1mg/kg) 5min before reperfusion in a murine myocardial IR model decreased infarct size by 48% after 24h of reperfusion. In addition, Tat-DAXXp was still efficient after a 30-min delayed administration, and was completely degraded and eliminated within 24h thereby reducing risks of potential side effects. Importantly, Tat-DAXXp reduced mouse early post-infarction mortality by 67%. Mechanistically, cardioprotection was supported by both anti-apoptotic and pro-survival effects, and an improvement of myocardial functional recovery as evidenced in ex vivo experiments. Conclusions Our study demonstrates that a single dose of Tat-DAXXp injected intravenously at the onset of reperfusion leads to a strong cardioprotection in vivo by inhibiting IR injury validating Tat-DAXXp as a promising candidate for therapeutic application.
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