Abstract 17767: Annexin-A1 Biomimetic Peptide Attenuates Myocardial Ischemia-Reperfusion Injury via Increased Sirtuin-3
Background: Mitochondria play critical roles in mediating apoptosis and necrosis following myocardial ischemia-reperfusion (IR). Annexin A1 has been implicated in cardioprotection through resolution of inflammation in part via regulation of histone deacetylation. Sirtuin 3 (SIRT3) is a class III histone deacetylase implicated in regulating mitochondrial oxidative phosphorylation and myocardial metabolism. We tested the hypothesis that an Annexin A1 biomimetic peptide (ANXA1sp) attenuates myocardial IR injury through differential upregulation of SIRT3 and preservation of mitochondrial function.
Methods: In vitro simulated IR: Adult rat ventricular cardiomyocytes (ARVCs, n=3) were exposed to 10 μM ANXA1sp for 1h, subjected to 2h oxygen-glucose deprivation (OGD). In vivo IR: Male rats (n=5) were subjected to 75 min of mild hypothermic cardiopulmonary bypass (CPB) with 45 min of cardioplegic arrest (CA), and randomly received vehicle or ANXA1sp (3 mg/kg, iv and in cardioplegia). Efficacy endpoints were assessed at 24h post-reoxygenation (ARVC) and post-reperfusion (rat), including necrosis (Troponin I) and apoptosis (TUNEL). SIRT3 and cytochrome c were measured in isolated mitochondria by Western blot.
Results: ANXA1sp significantly reduced IR injury both in ARVCs and myocardium as evidenced by significantly reduced myocardial necrosis and apoptosis (p<0.05). The observed cardio and cytoprotective effects were associated with increased mitochondrial expression SIRT3 (Figure A, B), maintained mitochondrial cytochrome c (Figure, B), and increased levels of ATP following IR stress (Figure C, D)
Conclusions: Cardioprotective effects of ANXA1sp following surgical IR are mediated in part by prosurvival mechanisms involving increased mitochondrial expression of SIRT3, preservation of mitochondrial integrity and dynamic function.
- © 2013 by American Heart Association, Inc.