Abstract 367: CGEN-855A, a Small Peptide Agonist of the Formyl Peptide Receptor-Like 1 Reduces Myocardial Reperfusion Injury
Background: Neutrophils (PMNs) mediate reperfusion injury in part. Reperfusion (R) accelerates the accumulation of PMNs into ischemic myocardium. Postconditioning (PC) inhibits PMN activation and accumulation in area at risk (AAR) myocardium. Formyl-peptide receptor-like1 (FPRL1) agonists directly inhibit PMN transmigration. Accordingly, this study tests the hypotheses that
the FPRL1 agonist CGEN-855A applied at R reduces infarct size by inhibition of PMN infiltration;
the infarct reduction by CGEN-855A is comparable to that of the mechanical intervention Postconditioning; and
since both CGEN-855A and PC share a common property of PMN inhibition, the combination of CGEN-855A and Postconditioning (PC) will not have an additive effect on infarct size reduction.
Methods: In anesthetized open-chest rats, the left coronary artery (LCA) was occluded for 30 min and reperfused for 3 hours. Rats (n=10) were randomly assigned to:
Control- equal volume vehicle 5 min before R;
PC: three cycles of 10-s R followed by 10-s re-occlusion during the first minute of R;
2 mg/kg CGEN-855A administered 5 min before R;
2 mg/kg CGEN-855A + PC at R.
Separate experiments were performed to assess PMN accumulation in AAR tissue by immunohistochemistry in control, CGEN-855A and PC groups.
Results: The AAR (% left ventricular mass, AAR/LV) was comparable among groups. Infarct size (necrosis as % AAR, AN/AAR), was significantly less in the PC (41.2 ± 2.7*) and CGEN-855A (43.6 ± 2.9*) groups vs Control (57.0 ± 2.3). There was no additive effect of the combination of CGEN-855A and PC at R (44.6 ± 1.3). Both CGEN-855A (30.1 ± 0.6/HPF) and PC (34.8 ± 1.5/HPF) significantly reduced PMN accumulation in AAR tissue vs control (43.2 ± 0.7/HPF).
stimulation of the FPRL1 with agonist CGEN-855A exerts cardioprotection at R by reducing infarct size;
CGEN-855A peptide inhibits PMN accumulation;
the extent of cardioprotection and PMN inhibition by CGEN-855A is similar to that of PC;
there is no additive effect of their combination, consistent with a similar physiological pathway of PMN inhibition.
*P< 0.05 vs Control