2420Effects of a selective small-molecule formyl peptide receptor 2 agonist on post myocardial inflammation and left ventricular structure-function relationships

Abstract

Abstract Background/Introduction Dysregulated inflammation following myocardial infarction (MI) can lead to maladaptive infarct healing, myocardial damage and heart failure. Formyl peptide receptor 2 (FPR2) plays an important role in the ligand-dependent regulation of inflammation resolution. Stimulation of resolution via FPR2 activation is hypothesized to preserve left ventricular (LV) structure-function relationships thereby preventing pathological cardiac remodeling, and heart failure. Purpose We evaluated a selective 4-phenylpyrrolidinone FPR2 agonist in rodent MI models by assessing the impact on LV and infarct scar remodeling and cardiac function. Methods The FPR2 agonist was evaluated in phagocytosis, chemotaxis and cytokine response assays. In vivo, following permanent occlusion of the left anterior descending (LAD) artery, C57BL/6 mice or Sprague-Dawley rats were treated with the FPR2 agonist or vehicle; PO gavage, QD. Treatment began 24 hours after occlusion (0.3 and 3 mg/kg) and continued for three days to assess early inflammation or four weeks to evaluate LV and infarct structure and function. Rats subjected to permanent MI were treated 48 hours after occlusion (0.01, 0.1. 1, 10 mg/kg) for six weeks to assess structure-function relationships. A parallel study in rats evaluated compound treatment (0.01, 0.1. 1, 10 mg/kg) following 60 minutes occlusion and reperfusion of the LAD artery. Results The FPR2 agonist enhanced cellular phagocytosis and chemotaxis, and stimulated IL-10 and MCP-1 gene expression in isolated human whole blood. In mice, FPR2 agonist treatment improved survival post MI, reduced LV chamber area and infarct size (26% and 55% vs. vehicle, respectively, P<0.05) and preserved infarct wall thickness (59% vs. vehicle, P<0.05). Treatment increased macrophage arginase 1 levels three days post-MI in the infarct border zone and CD206 levels in the whole heart, indicating a shift towards a pro-resolution phenotype. In rats, FPR2 agonist treatment preserved infarct wall thickness (maximal at 10 mg/kg, 96% vs. vehicle, P<0.05) and increased LV ejection fraction at all doses (+9% vs. vehicle, P<0.05). Following occlusion and reperfusion of the LAD artery, treatment preserved viable myocardium across the infarct wall at multiple doses (25–41%, P<0.05) resulting in increased ejection fraction (14% and 19% vs vehicle at 0.01 and 1 mg/kg, respectively, P<0.05). Conclusion(s) Improvements in cardiac structure-function versus vehicle treated animals support the concept that agonism of FPR2 improves post-MI wound healing, limiting adverse post-MI LV remodeling, thereby preserving cardiac function. These preclinical results suggest targeting FPR2 may present an innovative approach towards development of effective drug therapies to prevent heart failure post-MI. Acknowledgement/Funding Bristol-Myers Squibb Company