TD peptide as an adjunct of reperfusion therapy provides long-term cardioprotective effects in a mouse model of ischemia-reperfusion

Introduction During myocardial infarction (MI), reperfusion therapy 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 have developed a cardioprotective tool, the anti-apoptotic Tat-DAXXp (TD) peptide, targeting the FAS-dependent extrinsic pathway and recently evidenced as a potent therapeutic molecule. Objective The aim of the present study was to evaluate TD long-term cardioprotective effects in a mouse model of reperfused infarction. Methods TD peptide was evaluated in a mouse model of myocardial infarction (40 minutes ischemia) followed by reperfusion and 6 months follow-up. TD peptide (1 mg/kg) was administered in mice subjected to MI (TD; n = 21), 5 min prior to reperfusion. Cardiac injury in the study cohort was assessed by the quantification of cardiac Troponin I levels at 24 h post-MI and each month of the period. Pre-clinical evaluation was performed by the mean of echocardiographic follow-up using both conventional and strain parameters. A histological analysis was performed at the end of the protocol for the quantification of fibrosis extend. Results 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). Conclusion Targeting the extrinsic pathway with the TD peptide at the onset of reperfusion provided long-term cardioprotection in a mouse model of reperfused infarction by improving post-MI cardiac performance and preventing cardiac remodeling.