Author + information
- Received February 22, 2019
- Revision received July 16, 2019
- Accepted July 17, 2019
- Published online December 23, 2019.
- Ricardo A. García, PhDa,b,∗ (, )
- Bruce R. Ito, PhDb,
- John A. Lupisella, MSca,
- Nancy A. Carson, BSca,
- Mei-Yin Hsu, MSca,
- Gayani Fernando, MSca,
- Madeleine Heroux, PhDc,
- Michel Bouvier, PhDc,
- Elizabeth Dierks, PhDa,
- Ellen K. Kick, PhDa,
- David A. Gordon, PhDa,
- Jian Chen, PhDa,
- Gabe Mintier, BSca,
- Marilyn Carrier, PhDc,
- Stéphane St-Onge, MScc,
- Himanshu Shah, MSca,
- Jordan Towne, BScb,
- Marcela Sotelo Bucardo, BScb,
- Xiuying Ma, PhDa,
- Carol S. Ryan, BSca,
- Nicholas R. Wurtz, PhDa,
- Jacek Ostrowski, PhDa and
- Francisco J. Villarreal, MD, PhDb
- aDepartment of Cardiovascular and Fibrosis Drug Discovery, Bristol-Myers Squibb Company, Pennington, New Jersey
- bDepartment of Medicine, University of California San Diego, San Diego, California
- cInstitute for Research in Immunology and Cancer, Université de Montréal, Montréal, Québec, Canada
- ↵∗Address for correspondence:
Dr. Ricardo A. Garcia, Bristol-Myers Squibb Company, 311 Pennington-Rocky Hill Road, Pennington, New Jersey 08534.
• Myocardial infarction leads to recruitment of monocyte/macrophages to the injured myocardium to drive infarct healing.
• Activation of formyl peptide receptors (FPR1 and FPR2) present on macrophages contributes to key cellular activities that can potentiate wound healing.
• Myocardial infarction was induced in rodents to study the effects of long-term treatment with Compound 43, a small molecule agonist of FPR1 and FPR2.
• Main findings: Compound 43 stimulated proresolution macrophage activities, improved left ventricle and infarct structure, and preserved cardiac function post-myocardial infarction.
• The results suggest that stimulation of proresolution activities of FPRs can favorably alter post-myocardial infarction pathophysiology that leads to heart failure.
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.
This work was supported by Bristol-Myers Squibb (Princeton, NJ, USA). Bristol-Myers Squibb policy on data sharing may be found at https://www.bms.com/researchers-andpartners/independent-research/data-sharing-request-process.html. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose.
The authors attest they are in compliance with human studies committees and animal welfare regulations of the authors’ institutions and Food and Drug Administration guidelines, including patient consent where appropriate. For more information, visit the JACC: Basic to Translational Science author instructions page.
- Received February 22, 2019.
- Revision received July 16, 2019.
- Accepted July 17, 2019.
- 2019 The Authors