The G Protein Biased Small Molecule Apelin Agonist CMF-019 is Disease Modifying in Endothelial Cell Apoptosis In Vitro and Induces Vasodilatation Without Desensitisation In Vivo
Signaling through the apelin receptor is beneficial for a number of diseases including pulmonary arterial hypertension. The endogenous small peptides, apelin and elabela/toddler, are downregulated in pulmonary arterial hypertension but are not suitable for exogenous administration owing to a lack of...
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Frontiers Media S.A.
2021-01-01
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| Series: | Frontiers in Pharmacology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fphar.2020.588669/full |
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| author | Cai Read Duuamene Nyimanu Peiran Yang Rhoda E. Kuc Thomas L. Williams Christopher M. Fitzpatrick Richard Foster Robert C. Glen Robert C. Glen Janet J. Maguire Anthony P. Davenport |
| author_facet | Cai Read Duuamene Nyimanu Peiran Yang Rhoda E. Kuc Thomas L. Williams Christopher M. Fitzpatrick Richard Foster Robert C. Glen Robert C. Glen Janet J. Maguire Anthony P. Davenport |
| author_sort | Cai Read |
| collection | DOAJ |
| description | Signaling through the apelin receptor is beneficial for a number of diseases including pulmonary arterial hypertension. The endogenous small peptides, apelin and elabela/toddler, are downregulated in pulmonary arterial hypertension but are not suitable for exogenous administration owing to a lack of bioavailability, proteolytic instability and susceptibility to renal clearance. CMF-019, a small molecule apelin agonist that displays strong bias towards G protein signaling over β-arrestin (∼400 fold), may be more suitable. This study demonstrates that in addition to being a positive inotrope, CMF-019 caused dose-dependent vasodilatation in vivo (50 nmol 4.16 ± 1.18 mmHg, **p < 0.01; 500 nmol 6.62 ± 1.85 mmHg, **p < 0.01), without receptor desensitization. Furthermore, CMF-019 rescues human pulmonary artery endothelial cells from apoptosis induced by tumor necrosis factor α and cycloheximide (5.66 ± 0.97%, **p < 0.01) by approximately 50% of that observable with rhVEGF (11.59 ± 1.85%, **p < 0.01), suggesting it has disease-modifying potential in vitro. CMF-019 displays remarkable bias at the apelin receptor for a small molecule and importantly recapitulates all aspects of the cardiovascular responses to the endogenous ligand, [Pyr1]apelin-13, in vivo. Additionally, it is able to protect human pulmonary artery endothelial cells from apoptosis, suggesting that the beneficial effects observed with apelin agonists extend beyond hemodynamic alleviation and address disease etiology itself. These findings support CMF-019 as a G protein biased small molecule apelin agonist in vitro and in vivo that could form the basis for the design of novel therapeutic agents in chronic diseases, such as, pulmonary arterial hypertension. |
| first_indexed | 2024-12-22T20:27:32Z |
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| institution | Directory Open Access Journal |
| issn | 1663-9812 |
| language | English |
| last_indexed | 2024-12-22T20:27:32Z |
| publishDate | 2021-01-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Pharmacology |
| spelling | doaj.art-2d0660c081eb47399d2ca55e2ed4196f2022-12-21T18:13:41ZengFrontiers Media S.A.Frontiers in Pharmacology1663-98122021-01-011110.3389/fphar.2020.588669588669The G Protein Biased Small Molecule Apelin Agonist CMF-019 is Disease Modifying in Endothelial Cell Apoptosis In Vitro and Induces Vasodilatation Without Desensitisation In VivoCai Read0Duuamene Nyimanu1Peiran Yang2Rhoda E. Kuc3Thomas L. Williams4Christopher M. Fitzpatrick5Richard Foster6Robert C. Glen7Robert C. Glen8Janet J. Maguire9Anthony P. Davenport10Department of Medicine, Experimental Medicine and Immunotherapeutics, Addenbrooke’s Hospital, University of Cambridge, Cambridge, United KingdomDepartment of Medicine, Experimental Medicine and Immunotherapeutics, Addenbrooke’s Hospital, University of Cambridge, Cambridge, United KingdomDepartment of Medicine, Experimental Medicine and Immunotherapeutics, Addenbrooke’s Hospital, University of Cambridge, Cambridge, United KingdomDepartment of Medicine, Experimental Medicine and Immunotherapeutics, Addenbrooke’s Hospital, University of Cambridge, Cambridge, United KingdomDepartment of Medicine, Experimental Medicine and Immunotherapeutics, Addenbrooke’s Hospital, University of Cambridge, Cambridge, United KingdomSchool of Chemistry and Astbury Centre for Structural Biology, University of Leeds, Leeds, United KingdomSchool of Chemistry and Astbury Centre for Structural Biology, University of Leeds, Leeds, United KingdomDepartment of Chemistry, Centre for Molecular Informatics, University of Cambridge, Cambridge, United KingdomDivision of Systems Medicine, Department of Metabolism Digestion and Reproduction, Imperial College London, London, United KingdomDepartment of Medicine, Experimental Medicine and Immunotherapeutics, Addenbrooke’s Hospital, University of Cambridge, Cambridge, United KingdomDepartment of Medicine, Experimental Medicine and Immunotherapeutics, Addenbrooke’s Hospital, University of Cambridge, Cambridge, United KingdomSignaling through the apelin receptor is beneficial for a number of diseases including pulmonary arterial hypertension. The endogenous small peptides, apelin and elabela/toddler, are downregulated in pulmonary arterial hypertension but are not suitable for exogenous administration owing to a lack of bioavailability, proteolytic instability and susceptibility to renal clearance. CMF-019, a small molecule apelin agonist that displays strong bias towards G protein signaling over β-arrestin (∼400 fold), may be more suitable. This study demonstrates that in addition to being a positive inotrope, CMF-019 caused dose-dependent vasodilatation in vivo (50 nmol 4.16 ± 1.18 mmHg, **p < 0.01; 500 nmol 6.62 ± 1.85 mmHg, **p < 0.01), without receptor desensitization. Furthermore, CMF-019 rescues human pulmonary artery endothelial cells from apoptosis induced by tumor necrosis factor α and cycloheximide (5.66 ± 0.97%, **p < 0.01) by approximately 50% of that observable with rhVEGF (11.59 ± 1.85%, **p < 0.01), suggesting it has disease-modifying potential in vitro. CMF-019 displays remarkable bias at the apelin receptor for a small molecule and importantly recapitulates all aspects of the cardiovascular responses to the endogenous ligand, [Pyr1]apelin-13, in vivo. Additionally, it is able to protect human pulmonary artery endothelial cells from apoptosis, suggesting that the beneficial effects observed with apelin agonists extend beyond hemodynamic alleviation and address disease etiology itself. These findings support CMF-019 as a G protein biased small molecule apelin agonist in vitro and in vivo that could form the basis for the design of novel therapeutic agents in chronic diseases, such as, pulmonary arterial hypertension.https://www.frontiersin.org/articles/10.3389/fphar.2020.588669/fullapelinbiascardiovascularin vivoapoptosispulmonary artery endothelial cell |
| spellingShingle | Cai Read Duuamene Nyimanu Peiran Yang Rhoda E. Kuc Thomas L. Williams Christopher M. Fitzpatrick Richard Foster Robert C. Glen Robert C. Glen Janet J. Maguire Anthony P. Davenport The G Protein Biased Small Molecule Apelin Agonist CMF-019 is Disease Modifying in Endothelial Cell Apoptosis In Vitro and Induces Vasodilatation Without Desensitisation In Vivo Frontiers in Pharmacology apelin bias cardiovascular in vivo apoptosis pulmonary artery endothelial cell |
| title | The G Protein Biased Small Molecule Apelin Agonist CMF-019 is Disease Modifying in Endothelial Cell Apoptosis In Vitro and Induces Vasodilatation Without Desensitisation In Vivo |
| title_full | The G Protein Biased Small Molecule Apelin Agonist CMF-019 is Disease Modifying in Endothelial Cell Apoptosis In Vitro and Induces Vasodilatation Without Desensitisation In Vivo |
| title_fullStr | The G Protein Biased Small Molecule Apelin Agonist CMF-019 is Disease Modifying in Endothelial Cell Apoptosis In Vitro and Induces Vasodilatation Without Desensitisation In Vivo |
| title_full_unstemmed | The G Protein Biased Small Molecule Apelin Agonist CMF-019 is Disease Modifying in Endothelial Cell Apoptosis In Vitro and Induces Vasodilatation Without Desensitisation In Vivo |
| title_short | The G Protein Biased Small Molecule Apelin Agonist CMF-019 is Disease Modifying in Endothelial Cell Apoptosis In Vitro and Induces Vasodilatation Without Desensitisation In Vivo |
| title_sort | g protein biased small molecule apelin agonist cmf 019 is disease modifying in endothelial cell apoptosis in vitro and induces vasodilatation without desensitisation in vivo |
| topic | apelin bias cardiovascular in vivo apoptosis pulmonary artery endothelial cell |
| url | https://www.frontiersin.org/articles/10.3389/fphar.2020.588669/full |
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