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Selective FPR2 Agonism Promotes a Proresolution Macrophage Phenotype and Improves Cardiac Structure-Function Post Myocardial Infarction.

García RA, Lupisella JA, Ito BR, Hsu MY, Fernando G, Carson NL, Allocco JJ, Ryan CS, Zhang R, Wang Z, Heroux M, Carrier M, St-Onge S, Bouvier M, Dudhgaonkar S, Nagar J, Bustamante-Pozo MM, Garate-Carrillo A, Chen J, Ma X, Search DJ, Dierks EA, Kick EK, Wexler RR, Gordon DA, Ostrowski J, Wurtz NR, Villarreal F

Department of Cardiovascular and Fibrosis Drug Discovery, Bristol Myers Squibb, Princeton, New Jersey, USA.

Dysregulated inflammation following myocardial infarction (MI) leads to maladaptive healing and remodeling. The study characterized and evaluated a selective formyl peptide receptor 2 (FPR2) agonist BMS-986235 in cellular assays and in rodents undergoing MI. BMS-986235 activated G proteins and promoted β-arrestin recruitment, enhanced phagocytosis and neutrophil apoptosis, regulated chemotaxis, and stimulated interleukin-10 and monocyte chemoattractant protein-1 gene expression. Treatment with BMS-986235 improved mouse survival, reduced left ventricular area, reduced scar area, and preserved wall thickness. Treatment increased macrophage arginase-1 messenger RNA and CD206 receptor levels indicating a proresolution phenotype. In rats following MI, BMS-986235 preserved viable myocardium, attenuated left ventricular remodeling, and increased ejection fraction relative to control animals. Therefore, FPR2 agonism improves post-MI healing, limits remodeling and preserves function, and may offer an innovative therapeutic option to improve outcomes.

JACC Basic Transl Sci 2021;6(8):676-689.

Pubmed ID: 34466754

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