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

• DOI: 10.1016/j.jacbts.2021.07.007
• Publication Date: 2021-08-23T18:04:37Z
• Authors: Ricardo A. García; John A. Lupisella; Bruce R. Ito; Mei-Yin Hsu; Gayani Fernando; Nancy L. Carson; John J. Allocco; Carol S. Ryan; Rongan Zhang; Zhaoqing Wang; Madeleine Heroux; Marilyn Carrier; Stéphane St.-Onge; Michel Bouvier; Shailesh Dudhgaonkar; Jignesh Nagar; Moises M. Bustama...; Alejandra Garate-...; Jian Chen; Xiuying Ma; Debra J. Search; Elizabeth A. Dierks; Ellen K. Kick; Ruth R. Wexler; David A. Gordon; Jacek Ostrowski; Nicholas R. Wurtz; Francisco Villarreal
• Keywords: 0301 basic medicine; 03 medical and health sciences; Preclinical Research; 3. Good health

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.