Résumé
Introduction:Apoptosis is one of the main factors contributing to reperfusion injury after acute myocardial infarction. In this context, we were the first to evidence that the interaction between DAXX (death-associated protein adaptor protein) and FAS receptor plays a major role in reperfusion injury. Objective: The aim of our study was to evaluate the cardioprotective effects of the anti-apoptotic peptide Tat-DAXXp interfering with the FAS:DAXX pathway.Methods: Anesthetized mice were subjected to a surgical protocol of reversible coronary artery ligation and treated with Tat-DAXXp at the onset of reperfusion (IV injection). In the first cohort, cardiac injury was evaluated through infarct size measurement (TTC method) and apoptosis quantification (DNA fragmentation and Western blotting). In a second one, mice were followed up for 6 months to evaluate plasma cTnI levels, cardiac function by echocardiography (Vevo1100; Visualsonic), and postmortem myocardial fibrosis (red picrosirius staining). Results:A dose-response study allowed us to identify 1 mg/kg as the optimal dose of Tat-DAXXp providing a 48%-decrease in infarct size after 24 hours of reperfusion. The temporal time window of cardioprotection was defined as the first 30 minutes after the onset of reperfusion. A SPECT-CT study with an iodinated Tat-DAXXp isoform revealed that the therapeutic peptide was completely degraded and eliminated within 24 hours thereby reducing risks of potential side effects. Importantly, immediate post-infarction mortality was reduced by 67% by Tat-DAXXp treatment. Mechanistically, cardioprotection was supported by both anti-apoptotic and pro-survival effects, a decreased amount of cardiac fibrosis (-54%), an improvement of cardiac systolic function, and the prevention of LV remodeling after 6 months of reperfusion. Conclusion:Our study demonstrates that a single dose of Tat-DAXXp injected intravenously at the onset of reperfusion leads to strong cardioprotection in vivo by inhibiting ischemia-reperfusion injury, preventing cardiac remodeling, and restoring cardiac function.