Abstract 3007: Annexin-A1 Mimetic Peptide and PPAR-alpha Agonist Attenuate Hyperglycemic Exacerbation of Myocardial Ischemia/Reperfusion Injury Following Cardioplegic Arrest in the Rat
Background: Myocardial ischemia/reperfusion injury (MIRI), a major cause of morbidity and mortality following cardiac surgery, is further exacerbated by acute hyperglycemia (AHG). We tested the hypothesis that modulation of Annexin-A1 (ANXA1) and peroxisome proliferator-activated receptor alpha (PPARα) pathways attenuates AHG-induced MIRI through enhanced resolution of myocardial inflammation.
Methods: Male SD rats were assigned to 5 groups (N=3/group): cardioplegic arrest (CA), CA+AHG (CAHG), ANXA1 short peptide (ANXA1sp, 3mg/kg), PPARα agonist (Wy14643, 1mg/kg), and combination therapy (ANX1+Wy). AHG was induced using 25% Dextrose (5gm/kg), and glucose levels maintained >300 mg/dl. Animals underwent 75 min of CPB with 45 min of CA (blood cardioplegia). Severity of MIRI was assessed 24 hrs post-reperfusion as:
plasma levels of cardiac Troponin I (cTnI) and heart-type fatty acid binding protein (HFABP) by ELISA;
myocardial apoptosis - levels of cleaved caspase-3 (Western blot) and TUNEL staining;
myocardial NF-kB and PPARα DNA binding activities, levels of TNFα, IL6, and myeloperoxidase (MPO) activity by ELISA.
Results: AHG exacerbated perioperative myocardial necrosis and apoptosis, which were attenuated by ANXA1sp, Wy14643, and their combination (Table⇓). These cardioprotective effects were mediated via down-regulation of NF-kB and up-regulation of PPARα, leading to decreased myocardial levels of TNF-α and IL-6, and reduced neutrophil extravasation. In treated animals, increased physical binding of both ANXA1 and PPARα to the NF-kB p65 subunit was identified by co-IP and confocal microscopy.
Conclusions: A novel ANXA1 short peptide and a selective PPARα agonist are cardioprotective against hyperglycemic exacerbation of MIRI in the setting of CA. Both compounds enhance resolution of myocardial inflammation through deregulation of NF-kB mediated inflammatory and apoptotic signaling pathways as well as neutrophil transmigration.