Cardioprotective Actions of the Annexin-A1 N-Terminal Peptide, Ac2-26, Against Myocardial Infarction

Abstract

The anti-inflammatory, pro-resolving annexin-A1 protein acts as an endogenous brake against exaggerated cardiac necrosis, inflammation, and fibrosis following myocardial infarction (MI) <i>in vivo</i>. Little is known, however, regarding the cardioprotective actions of the N-terminal-derived peptide of annexin A1, Ac_2-26, particularly beyond its anti-necrotic actions in the first few hours after an ischemic insult. In this study, we tested the hypothesis that exogenous Ac_2-26 limits cardiac injury <i>in vitro</i> and <i>in vivo.</i> Firstly, we demonstrated that Ac_2-26 limits cardiomyocyte death both <i>in vitro</i> and in mice subjected to ischemia-reperfusion (I-R) injury <i>in vivo</i> (Ac_2-26, 1 mg/kg, i.v. just prior to post-ischemic reperfusion). Further, Ac_2-26 (1 mg/kg i.v.) reduced cardiac inflammation (after 48 h reperfusion), as well as both cardiac fibrosis and apoptosis (after 7-days reperfusion). Lastly, we investigated whether Ac_2-26 preserved cardiac function after MI. Ac_2-26 (1 mg/kg/day s.c., osmotic pump) delayed early cardiac dysfunction 1 week post MI, but elicited no further improvement 4 weeks after MI. Taken together, our data demonstrate the first evidence that Ac_2-26 not only preserves cardiomyocyte survival <i>in vitro</i>, but also offers cardioprotection beyond the first few hours after an ischemic insult <i>in vivo</i>. Annexin-A1 mimetics thus represent a potential new therapy to improve cardiac outcomes after MI.