A novel therapeutic peptide targeting myocardial reperfusion injury

被引:14
作者
Boisguerin, Prisca [1 ,2 ]
Covinhes, Aurelie [3 ,4 ]
Gallot, Laura [3 ,4 ]
Barrere, Christian [3 ,4 ]
Vincent, Anne [3 ,4 ]
Busson, Muriel [5 ]
Piot, Christophe [3 ,4 ,6 ]
Nargeot, Joel [3 ,4 ]
Lebleu, Bernard [2 ]
Barrere-Lemaire, Stephanie [3 ,4 ]
机构
[1] Univ Montpellier, CNRS, CRBM, F-34293 Montpellier, France
[2] Univ Montpellier, CNRS, DIMNP, F-34095 Montpellier, France
[3] Univ Montpellier, INSERM, CNRS, IGF, F-34094 Montpellier, France
[4] Lab Excellence Ion Channel Sci & Therapeut, F-06560 Valbonne, France
[5] Univ Montpellier, INSERM, IRCM, F-34298 Montpellier, France
[6] Clin Millenaire, Dept Cardiol Intervent, F-34000 Montpellier, France
关键词
Cardioprotection; Apoptosis; Reperfusion Injury; Therapeutic peptide; DAXX; SIGNAL-TRANSDUCTION PATHWAY; CELL-DEATH; ISCHEMIA/REPERFUSION INJURY; HYDROGEN-PEROXIDE; DAXX TRAFFICKING; INFARCT SIZE; RAT HEARTS; PROTEIN; APOPTOSIS; STRESS;
D O I
10.1093/cvr/cvz145
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
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.
引用
收藏
页码:633 / 644
页数:12
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