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Small-molecule-biased formyl peptide receptor agonist compound 17b protects against myocardial ischaemia-reperfusion injury in mice.

ABSTRACT: Effective treatment for managing myocardial infarction (MI) remains an urgent, unmet clinical need. Formyl peptide receptors (FPR) regulate inflammation, a major contributing mechanism to cardiac injury following MI. Here we demonstrate that FPR1/FPR2-biased agonism may represent a novel therapeutic strategy for the treatment of MI. The small-molecule FPR1/FPR2 agonist, Compound 17b (Cmpd17b), exhibits a distinct signalling fingerprint to the conventional FPR1/FPR2 agonist, Compound-43 (Cmpd43). In Chinese hamster ovary (CHO) cells stably transfected with human FPR1 or FPR2, Compd17b is biased away from potentially detrimental FPR1/2-mediated calcium mobilization, but retains the pro-survival signalling, ERK1/2 and Akt phosphorylation, relative to Compd43. The pathological importance of the biased agonism of Cmpd17b is demonstrable as superior cardioprotection in both in vitro (cardiomyocytes and cardiofibroblasts) and MI injury in mice in vivo. These findings reveal new insights for development of small molecule FPR agonists with an improved cardioprotective profile for treating MI.

SUBMITTER: Qin CX

PROVIDER: S-EPMC5309721 | biostudies-literature | 2017 Feb

REPOSITORIES: biostudies-literature

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Small-molecule-biased formyl peptide receptor agonist compound 17b protects against myocardial ischaemia-reperfusion injury in mice.

Qin Cheng Xue CX May Lauren T LT Li Renming R Cao Nga N Rosli Sarah S Deo Minh M Alexander Amy E AE Horlock Duncan D Bourke Jane E JE Yang Yuan H YH Stewart Alastair G AG Kaye David M DM Du Xiao-Jun XJ Sexton Patrick M PM Christopoulos Arthur A Gao Xiao-Ming XM Ritchie Rebecca H RH

Nature communications 20170207

Effective treatment for managing myocardial infarction (MI) remains an urgent, unmet clinical need. Formyl peptide receptors (FPR) regulate inflammation, a major contributing mechanism to cardiac injury following MI. Here we demonstrate that FPR1/FPR2-biased agonism may represent a novel therapeutic strategy for the treatment of MI. The small-molecule FPR1/FPR2 agonist, Compound 17b (Cmpd17b), exhibits a distinct signalling fingerprint to the conventional FPR1/FPR2 agonist, Compound-43 (Cmpd43). ...[more]

PMID: 28169296

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Project description:Aims:Myocardial ischaemia followed by reperfusion (IR) causes an oxidative burst resulting in cellular dysfunction. Little is known about the impact of oxidative stress on cardiomyocyte lipids and their role in cardiac cell death. Our goal was to identify oxidized phosphatidylcholine-containing phospholipids (OxPL) generated during IR, and to determine their impact on cell viability and myocardial infarct size. Methods and results:OxPL were quantitated in isolated rat cardiomyocytes using mass spectrophotometry following 24 h of IR. Cardiomyocyte cell death was quantitated following exogenously added OxPL and in the absence or presence of E06, a 'natural' murine monoclonal antibody that binds to the PC headgroup of OxPL. The impact of OxPL on mitochondria in cardiomyocytes was also determined using cell fractionation and Bnip expression. Transgenic Ldlr-/- mice, overexpressing a single-chain variable fragment of E06 (Ldlr-/--E06-scFv-Tg) were used to assess the effect of inactivating endogenously generated OxPL in vivo on myocardial infarct size. Following IR in vitro, isolated rat cardiomyocytes showed a significant increase in the specific OxPLs PONPC, POVPC, PAzPC, and PGPC (P < 0.05 to P < 0.001 for all). Exogenously added OxPLs resulted in significant death of rat cardiomyocytes, an effect inhibited by E06 (percent cell death with added POVPC was 22.6 ± 4.14% and with PONPC was 25.3 ± 3.4% compared to 8.0 ± 1.6% and 6.4 ± 1.0%, respectively, with the addition of E06, P < 0.05 for both). IR increased mitochondrial content of OxPL in rat cardiomyocytes and also increased expression of Bcl-2 death protein 3 (Bnip3), which was inhibited in presence of E06. Notably cardiomyocytes with Bnip3 knock-down were protected against cytotoxic effects of OxPL. In mice exposed to myocardial IR in vivo, compared to Ldlr-/- mice, Ldlr-/--E06-scFv-Tg mice had significantly smaller myocardial infarct size normalized to area at risk (72.4 ± 21.9% vs. 47.7 ± 17.6%, P = 0.023). Conclusions:OxPL are generated within cardiomyocytes during IR and have detrimental effects on cardiomyocyte viability. Inactivation of OxPL in vivo results in a reduction of infarct size.

Project description:The alterations in mitochondrial protein glycosylation in myocardial ischaemia reperfusion (I/R) injury are still unclear. Therefore, based on a lectin microarray and liquid chromatograph-mass spectrometer/mass spectrometer (LC‒MS/MS) technology combined with a bioinformatics analysis, we studied the changes in mitochondrial protein glycosylation during I/R injury. This study revealed significant differences in mitochondrial glycoprotein during I/R injury. Compared with the sham operation group, the model group, which underwent ischaemia for 30 min, showed a high expression of glycan structures recognized by lectins, such as WFA, PTL-I, LTL, GSL-I, SBA and SNA, and a low expression of glycan structures recognized by ConA, VVA and RCA120. The model group, which underwent ischaemia for 45 min, showed a high expression of glycan structures recognized by LTL and SNA and a low expression of glycan structures recognized by ECA. Further analysis showed that the Siaα2-6Gal/N-acetylgalactosamine (GalNAc) structures recognized by SNA were significantly increased. In total, 91 differential proteins were identified by LC‒MS/MS, and 8 hub genes were screened by Gene Ontology (GO) enrichment, Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment and protein interaction analyses. Compared with the Gene Expression Omnibus (GEO) database genes, two differential genes, Pros1 and Vtn, were obtained. Pros1 is a key regulator of the inflammatory response and vascular injury response. The Vtn gene variant is associated with the risk of myocardial infarction. This study is expected to provide a new method for the treatment of I/R injury and could provide new ideas for the postoperative prognosis of patients. Highlights • Changes in the mitochondrial glycoprotein glycan profile in Myocardial Ischaemia Reperfusion Injury.• Expression of Siaα2-6Gal/GalNAc structures recognized by SNA increased in the process of I/R injury.• Proteins identified by LC‒MS/MS in the sham-operated group and the 30-min ischaemia group.• By comparison with the GEO database, two candidate genes, Pros1 and Vtn, were obtained.

Dataset Information

Small-molecule-biased formyl peptide receptor agonist compound 17b protects against myocardial ischaemia-reperfusion injury in mice.

Publications

Small-molecule-biased formyl peptide receptor agonist compound 17b protects against myocardial ischaemia-reperfusion injury in mice.

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