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

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

doi:10.1016/j.jacbts.2019.07.005

Cited by 38 publications

(45 citation statements)

References 42 publications

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“…Mice deficient in individual Fprs show not only an increased susceptibility to microbial infections but also a delayed tissue repair [7,24,25]. In addition, a recent study has elegantly demonstrated that activation of FPRs improves cardiac function in a post myocardial infarction model [26], suggesting an anti-inflammatory/pro-resolving role of FPR agonists.…”

Section: Introductionmentioning

confidence: 99%

Functional selective FPR1 signaling in favor of an activation of the neutrophil superoxide generating NOX2-complex

Lind

Holmdahl

Olofsson

et al. 2020

Preprint

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Two formyl peptide receptors (FPR1 and FPR2), abundantly expressed by neutrophils, regulate both pro-inflammatory tissue recruitment of neutrophils and resolution of inflammatory reactions. This dual functionality of the FPRs, opens for a possibility to develop receptor selective therapeutics as mechanism for novel anti-inflammatory treatments. In line with this, high throughput screening studies have identified numerous FPR ligands belonging to different structural classes, but a potent FPR1 agonist with defined biased signaling and functional selectivity has not yet been reported. In this study, we used an FPR1 selective small compound agonist (RE) that represents a chemical entity developed from NOX2 activators identified from our earlier screening studies (WO2012127214). This FPR1 agonist potently activates neutrophils to produce reactive oxygen species (ROS, EC50 ~1 nM), whereas it is a weaker chemoattractant than the prototype FPR1 agonist fMLF. At the signaling level, RE has a strong bias towards the PLC-PIP2-Ca 2+ pathway and ERK1/2 activation but away from β-arrestin recruitment and the ability to recruit neutrophils chemotactically. In addition, FPR1 when activated by RE could crossregulate other receptor-mediated neutrophil functions. In comparison to the peptide agonist fMLF, RE is more resistant to oxidization-induced inactivation by the MPO-H2O2-halide system. In summary, this study describes as a novel FPR1 agonist displaying a biased signaling and functional selectivity when activating FPR1 in human blood neutrophils. RE could possibly be a useful tool compound not only for further mechanistic studies of the regulatory role of FPR1 in inflammation in vitro and in vivo, but also for developing FPR1specific drug therapeutics.

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Section: Introductionmentioning

confidence: 99%

Functional selective FPR1 signaling in favor of an activation of the neutrophil superoxide generating NOX2-complex

Lind

Holmdahl

Olofsson

et al. 2020

Preprint

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“…Depending on the agonists examined, the signals generated by FPR2 mediate primarily pro-inflammatoryactivities, yet anti-inflammatory activities have also been described [8][9][10][11]. Based on the important roles of FPR2 in host defense and regulation of inflammation, this GPCR has been considered as a promising drug target for inflammatory conditions including cardiovascular diseases [12,13]. FPR2 transduces signaling primarily through heterotrimeric Gi/o proteins and the dissociated G subunits trigger activation of phospholipase C (PLC) associated with an increase in intracellular Ca 2+ [5,7].…”

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confidence: 99%

Barbadin selectively modulates FPR2-mediated neutrophil functions independent of receptor endocytosis

Sundqvist

Holdfeldt

Wright

et al. 2020

Preprint

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Running title: Barbadin modulates specific neutrophil functions Abbreviations: Aoc = 2-aminooctanoic acid; AF = Alexa Fluor; AP2 = clathrin adaptor protein 2; AUC = area under the curve; BRET = bioluminescence resonance energy transfer; BSA = bovine serum albumin; CL = chemiluminescence; DMEM = Dulbecco's modified Eagle medium; DMSO = dimethyl sulfoxide; DPBS = Dulbecco's phosphate-buffered saline; FPR = formyl peptide receptor; GPCR = G protein-coupled receptor; HBSS = Hank's balanced salt solution; HRP = horseradish peroxidase; Lau = Lauroyl; KRG = Krebs-Ringer phosphate buffer: MOI = multiplicity of infection; MPO = myeloperoxidase; βNPhe = N-phenylmethylβ-alanine; βNrpe = N-(R)-1-phenylethyl-β-alanine; PFA = paraformaldehyde; PKC = protein kinase C; PLC = phospholipase C; PMA = phorbol 12-myristate 13-acetate; RhB = rhodamine B; RT = room temperature; ROS = reactive oxygen species; SOD = superoxide dismutase; TR-FRET = time-resolved förster resonance energy transfer AbstractFormyl peptide receptor 2 (FPR2), a member of the family of G protein-coupled receptors (GPCRs), mediates neutrophil migration, a response that has been linked to -arrestin recruitment. -Arrestin regulates GPCR endocytosis and can also elicit non-canonical receptor signaling. To determine the poorly understood role of β-arrestin in FPR2 endocytosis and in NADPH-oxidase activation in neutrophils, Barbadin was used as a research tool in this study.Barbadin has been shown to bind the clathrin adaptor protein (AP2) and thereby prevent arrestin/AP2 interaction and -arrestin-mediated GPCR endocytosis. In agreement with this, AP2/-arrestin interaction induced by an FPR2-specific agonist was inhibited by Barbadin.Unexpectedly, however, Barbadin did not inhibit FPR2 endocytosis, indicating that a mechanism independent of -arrestin/AP2 interaction may sustain FPR2 endocytosis. This was confirmed by the fact, that FPR2 also underwent agonist-promoted endocytosis in -arrestin deficient cells, albeit at a diminished level as compared to wild type cells. Dissection of the Barbadin effects on FPR2-mediated neutrophil functions including NADPH-oxidase activation mediated release of reactive oxygen species (ROS) and chemotaxis reveled that Barbadin had no effect on chemotactic migration whereas the release of ROS was potentiated/primed. The effect of Barbadin on ROS production was reversible, independent of -arrestin recruitment, and similar to that induced by latrunculin A. Taken together, our data demonstrate that endocytic uptake of FPR2 occurs independently of -arrestin, while Barbadin selectively augments FPR2-mediated neutrophil ROS production independently of receptor endocytosis.Given that Barbadin binds to AP2 and prevents the AP2/-arrestin interaction, our results indicate a role for AP2 in FPR2-mediated ROS release from human neutrophils. a large number of ligands belonging to different chemical classes [5][6][7]. Depending on the agonists examined, the signals generated by FPR2 mediate primarily pro-inflammatoryactivities, yet anti-in...

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“…In this issue of JACC: Basic to Translational Science , García et al. (2) explore the use of formyl peptide receptor (FPR) agonist, Compound 43 (Cmpd43), as a therapeutic agent that targets pattern recognition receptors to promote a more favorable immunological response and improve infarct healing.…”

mentioning

confidence: 99%

“…García et al. (2) focus on modulating recruited monocytes toward a proresolution phenotype to expedite tissue healing with Cmpd43—a dual FPR1/FPR2 agonist (4). Using in vitro assays, the authors first determined the role of FPR agonism by Cmpd43 on key macrophage functions of chemotaxis, phagocytosis, and cytokine release via receptors FPR1 and FPR2 separately.…”

mentioning

confidence: 99%

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Therapeutic Treatment Approaches Post–Myocardial Infarction

Zaman

Epelman

2019

JACC: Basic to Translational Science

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

Abstract: Visual Abstract

Cited by 38 publications

References 42 publications

Functional selective FPR1 signaling in favor of an activation of the neutrophil superoxide generating NOX2-complex

Functional selective FPR1 signaling in favor of an activation of the neutrophil superoxide generating NOX2-complex

Barbadin selectively modulates FPR2-mediated neutrophil functions independent of receptor endocytosis

Therapeutic Treatment Approaches Post–Myocardial Infarction

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