Abstract
Reperfusion therapy during myocardial infarction (MI) leads to side effects called ischemia–reperfusion (IR) injury for which no treatment exists. While most studies have targeted the intrinsic apoptotic pathway to prevent IR injury with no successful clinical translation, we evidenced recently the potent cardioprotective effect of the anti-apoptotic Tat-DAXXp (TD) peptide targeting the FAS-dependent extrinsic pathway. The aim of the present study was to evaluate TD long term cardioprotective effects against IR injury in a MI mouse model. TD peptide (1 mg/kg) was administered in mice subjected to MI (TD; n = 21), 5 min prior to reperfusion, and were clinically followed-up during 6 months after surgery. Plasma cTnI concentration evaluated 24 h post-MI was 70%-decreased in TD (n = 16) versus Ctrl (n = 20) mice (p***). Strain echocardiography highlighted a 24%-increase (p****) in the ejection fraction mean value in TD-treated (n = 12) versus Ctrl mice (n = 17) during the 6 month-period. Improved cardiac performance was associated to a 54%-decrease (p**) in left ventricular fibrosis at 6 months in TD (n = 16) versus Ctrl (n = 20). In conclusion, targeting the extrinsic pathway with TD peptide at the onset of reperfusion provided long-term cardioprotection in a mouse model of myocardial IR injury by improving post-MI cardiac performance and preventing cardiac remodeling.
Highlights
Reperfusion therapy during myocardial infarction (MI) leads to side effects called ischemia–reperfusion (IR) injury for which no treatment exists
For the patients that survive after MI, the morbidity leading to heart failure (HF) is rising leading to increased cost burden on the healthcare system
For the first time through a 6-month follow-up in a mouse model of myocardial ischemia–reperfusion (IR) injury, the long-term cardioprotective effects of the anti-apoptotic Tat-DAXXp (TD) peptide injected as an intravenous bolus (1 mg/kg body weight)
Summary
Reperfusion therapy during myocardial infarction (MI) leads to side effects called ischemia–reperfusion (IR) injury for which no treatment exists. Targeting the extrinsic pathway with TD peptide at the onset of reperfusion provided long-term cardioprotection in a mouse model of myocardial IR injury by improving post-MI cardiac performance and preventing cardiac remodeling. We have capitalized on the pro-apoptotic key role of the FAS death receptor in the extrinsic pathway since elevated Fas Ligand in the blood of AMI patients activates FAS r eceptor[6]. In this context, the death domain associated protein (DAXX) has been identified as a key element involved in IR injury in many organs including the heart[13,14,15]. Cytosolic pro-apoptotic DAXX protein binds to the intracellular part of the First Apoptosis Signal (FAS) death-receptor and activates the downstream apoptotic signaling p athway[22]
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