Cardioprotective effects of a synthetic peptide targeting the extrinsic apoptotic pathway in a mouse model of ischemia-reperfusion
| العنوان: | Cardioprotective effects of a synthetic peptide targeting the extrinsic apoptotic pathway in a mouse model of ischemia-reperfusion |
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| المؤلفون: | Muriel Busson, Anne Vincent, Christophe Piot, Christian Barrère, Joël Nargeot, Stéphanie Barrère-Lemaire, Bernard Lebleu, Aurélie Covinhes, Laura Gallot, Prisca Boisguerin |
| المساهمون: | Centre de recherche en Biologie Cellulaire (CRBM), Université Montpellier 2 - Sciences et Techniques (UM2)-Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM)-Université Montpellier 1 (UM1), Institut de Génomique Fonctionnelle (IGF), Université de Montpellier (UM)-Université Montpellier 1 (UM1)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Montpellier 2 - Sciences et Techniques (UM2)-Centre National de la Recherche Scientifique (CNRS), LabEx Ion Channel Science and Therapeutics, Institut de Recherche en Cancérologie de Montpellier (IRCM - U1194 Inserm - UM), CRLCC Val d'Aurelle - Paul Lamarque-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Clinique du Millénaire - Oc Santé [Montpellier], Oc Santé [Montpellier], Dynamique des interactions membranaires normales et pathologiques (DIMNP), Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM)-Université Montpellier 2 - Sciences et Techniques (UM2)-Université Montpellier 1 (UM1) |
| المصدر: | Archives of cardiovascular diseases Archives of cardiovascular diseases, Elsevier/French Society of Cardiology, 2019, 11 (2), pp.211. ⟨10.1016/j.acvdsp.2019.02.065⟩ |
| بيانات النشر: | HAL CCSD, 2019. |
| سنة النشر: | 2019 |
| مصطلحات موضوعية: | chemistry.chemical_classification, Cardioprotection, business.industry, [SDV]Life Sciences [q-bio], infarction, Ischemia, apoptosis, Peptide, Pharmacology, medicine.disease, ischemia-reperfusion, peptide, 3. Good health, Death-associated protein 6, chemistry, [SDV.MHEP.CSC]Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system, In vivo, Apoptosis, medicine, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, Cardiology and Cardiovascular Medicine, business, Reperfusion injury, Ex vivo, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology |
| الوصف: | Introduction Apoptosis is a main contributor of myocardial reperfusion injury during acute infarction. In a previous study, we showed that reperfusion injury was mediated by the FAS-dependent apoptotic signal mobilizing the DAXX (death-associated protein) adaptor protein. Objective To evaluate the cardioprotective effects of a synthetic peptide that uncouples FAS to the DAXX downstream pathway. Methods The SPOT technology was used to design a synthetic peptide interfering with FAS:DAXX interaction. This peptide was coupled to the Tat cell penetrating peptide (Tat-DAXXp). Infarct size (TTC staining) and apoptosis (DNA fragmentation) were evaluated in the left ventricle of mice subjected to a surgical protocol of reversible coronary artery ligation and treated by the peptide at the onset of reperfusion. Cellular internalization of the peptide was measured using a fluorescent peptide both in primary cultures of cardiomyocytes or in left ventricles after surgery. Results Anti-apoptotic properties of the synthetic peptide were demonstrated in primary cardiomyocytes. In vivo, one bolus of Tat-DAXXp (1 mg/kg), injected intravenously 5 min before reperfusion in a murine myocardial ischemia-reperfusion model decreased infarct size by 48% after 24 hours of reperfusion. After a 30-min delayed administration, Tat-DAXXp was still able to protect against reperfusion-induced apoptosis and was completely degraded and eliminated within 24 hours thereby reducing risks of potential side effects. Importantly, post-infarction mortality was reduced by 67% by Tat-DAXXp treatment. 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. Conclusion 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 ischemia-reperfusion injury. |
| اللغة: | English |
| تدمد: | 1875-2136 |
| الوصول الحر: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::56e139dfddaa9a34e50cbafb906daf51Test https://hal.archives-ouvertes.fr/hal-02404659Test |
| حقوق: | OPEN |
| رقم الانضمام: | edsair.doi.dedup.....56e139dfddaa9a34e50cbafb906daf51 |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 18752136 |
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