Preservation of Post-Infarction Cardiac Structure and Function via Long-Term Oral Formyl Peptide Receptor Agonist Treatment

Ricardo A García; Bruce R Ito; John A Lupisella; Nancy A Carson; Mei-Yin Hsu; Gayani Fernando; Madeleine Heroux; Michel Bouvier; Elizabeth Dierks; Ellen K Kick; David A Gordon; Jian Chen; Gabe Mintier; Marilyn Carrier; Stéphane St-Onge; Himanshu Shah; Jordan Towne; Marcela Sotelo Bucardo; Xiuying Ma; Carol S Ryan; Nicholas R Wurtz; Jacek Ostrowski; Francisco J Villarreal

doi:10.1016/j.jacbts.2019.07.005

Preservation of Post-Infarction Cardiac Structure and Function via Long-Term Oral Formyl Peptide Receptor Agonist Treatment

JACC Basic Transl Sci. 2019 Nov 13;4(8):905-920. doi: 10.1016/j.jacbts.2019.07.005. eCollection 2019 Dec.

Authors

Ricardo A García^{1

2}, Bruce R Ito², John A Lupisella¹, Nancy A Carson¹, Mei-Yin Hsu¹, Gayani Fernando¹, Madeleine Heroux³, Michel Bouvier³, Elizabeth Dierks¹, Ellen K Kick¹, David A Gordon¹, Jian Chen¹, Gabe Mintier¹, Marilyn Carrier³, Stéphane St-Onge³, Himanshu Shah¹, Jordan Towne², Marcela Sotelo Bucardo², Xiuying Ma¹, Carol S Ryan¹, Nicholas R Wurtz¹, Jacek Ostrowski¹, Francisco J Villarreal²

Affiliations

¹ Department of Cardiovascular and Fibrosis Drug Discovery, Bristol-Myers Squibb Company, Pennington, New Jersey.
² Department of Medicine, University of California San Diego, San Diego, California.
³ Institute for Research in Immunology and Cancer, Université de Montréal, Montréal, Québec, Canada.

Abstract

Dysregulated inflammation following myocardial infarction (MI) promotes left ventricular (LV) remodeling and loss of function. Targeting inflammation resolution by activating formyl peptide receptors (FPRs) may limit adverse remodeling and progression towards heart failure. This study characterized the cellular and signaling properties of Compound 43 (Cmpd43), a dual FPR1/FPR2 agonist, and examined whether Cmpd43 treatment improves LV and infarct remodeling in rodent MI models. Cmpd43 stimulated FPR1/2-mediated signaling, enhanced proresolution cellular function, and modulated cytokines. Cmpd43 increased LV function and reduced chamber remodeling while increasing proresolution macrophage markers. The findings demonstrate that FPR agonism improves cardiac structure and function post-MI.

Keywords: Cmpd43, Compound 43; Compound 43; FPR, formyl peptide receptor; HF, heart failure; IL, interleukin; IR, ischemia–reperfusion; KO, knockout; LAD, left anterior descending; LV, left ventricular; MI, myocardial infarction; PV, pressure–volume; SAA, serum amyloid A; WT, wild-type; agonist; formyl peptide receptor; heart failure; myocardial infarction.