A novel therapeutic peptide targeting myocardial reperfusion injury.

Abstract:

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 (1 mg/kg) 5 min before reperfusion in a murine myocardial IR model decreased infarct size by 48% after 24 h of reperfusion. In addition, Tat-DAXXp was still efficient after a 30-min delayed administration, and was completely degraded and eliminated within 24 h 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.

journal_name

Cardiovasc Res

journal_title

Cardiovascular research

authors

Boisguérin P,Covinhes A,Gallot L,Barrère C,Vincent A,Busson M,Piot C,Nargeot J,Lebleu B,Barrère-Lemaire S

doi

10.1093/cvr/cvz145

subject

Has Abstract

pub_date

2020-03-01 00:00:00

pages

633-644

issue

3

eissn

0008-6363

issn

1755-3245

pii

5506627

journal_volume

116

pub_type

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