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Research ArticleCardiovascular

A Phenyl-Pyrrolidine Derivative Reveals a Dual Inhibition Mechanism of Myocardial Mitochondrial Permeability Transition Pore, Which Is Limited by Its Myocardial Distribution

Mathieu Panel, Abdelhakim Ahmed-Belkacem, Isaac Ruiz, Jean-François Guichou, Jean-Michel Pawlotsky, Bijan Ghaleh and Didier Morin
Journal of Pharmacology and Experimental Therapeutics March 2021, 376 (3) 348-357; DOI: https://doi.org/10.1124/jpet.120.000359
Mathieu Panel
U955 - IMRB, Inserm, UPEC, Ecole Nationale Vétérinaire d’Alfort, Créteil, France (M.P., B.G., D.M.);Université Paris-Est, UMR S955, UPEC, Créteil, France (A.A.B., I.R., J.M.P.); INSERM U955, Team « Viruses, Hepatology, Cancer », Hôpital Henri Mondor, Créteil, France (A.A.B., J.M.P., I.R.); Centre de Biochimie Structurale (CBS), INSERM U1054, CNRS UMR5048, Université de Montpellier, Montpellier, France (J.F.G.); and Department of Virology, Hôpital Henri Mondor, Créteil, France (J.M.P.)
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Abdelhakim Ahmed-Belkacem
U955 - IMRB, Inserm, UPEC, Ecole Nationale Vétérinaire d’Alfort, Créteil, France (M.P., B.G., D.M.);Université Paris-Est, UMR S955, UPEC, Créteil, France (A.A.B., I.R., J.M.P.); INSERM U955, Team « Viruses, Hepatology, Cancer », Hôpital Henri Mondor, Créteil, France (A.A.B., J.M.P., I.R.); Centre de Biochimie Structurale (CBS), INSERM U1054, CNRS UMR5048, Université de Montpellier, Montpellier, France (J.F.G.); and Department of Virology, Hôpital Henri Mondor, Créteil, France (J.M.P.)
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Isaac Ruiz
U955 - IMRB, Inserm, UPEC, Ecole Nationale Vétérinaire d’Alfort, Créteil, France (M.P., B.G., D.M.);Université Paris-Est, UMR S955, UPEC, Créteil, France (A.A.B., I.R., J.M.P.); INSERM U955, Team « Viruses, Hepatology, Cancer », Hôpital Henri Mondor, Créteil, France (A.A.B., J.M.P., I.R.); Centre de Biochimie Structurale (CBS), INSERM U1054, CNRS UMR5048, Université de Montpellier, Montpellier, France (J.F.G.); and Department of Virology, Hôpital Henri Mondor, Créteil, France (J.M.P.)
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Jean-François Guichou
U955 - IMRB, Inserm, UPEC, Ecole Nationale Vétérinaire d’Alfort, Créteil, France (M.P., B.G., D.M.);Université Paris-Est, UMR S955, UPEC, Créteil, France (A.A.B., I.R., J.M.P.); INSERM U955, Team « Viruses, Hepatology, Cancer », Hôpital Henri Mondor, Créteil, France (A.A.B., J.M.P., I.R.); Centre de Biochimie Structurale (CBS), INSERM U1054, CNRS UMR5048, Université de Montpellier, Montpellier, France (J.F.G.); and Department of Virology, Hôpital Henri Mondor, Créteil, France (J.M.P.)
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Jean-Michel Pawlotsky
U955 - IMRB, Inserm, UPEC, Ecole Nationale Vétérinaire d’Alfort, Créteil, France (M.P., B.G., D.M.);Université Paris-Est, UMR S955, UPEC, Créteil, France (A.A.B., I.R., J.M.P.); INSERM U955, Team « Viruses, Hepatology, Cancer », Hôpital Henri Mondor, Créteil, France (A.A.B., J.M.P., I.R.); Centre de Biochimie Structurale (CBS), INSERM U1054, CNRS UMR5048, Université de Montpellier, Montpellier, France (J.F.G.); and Department of Virology, Hôpital Henri Mondor, Créteil, France (J.M.P.)
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Bijan Ghaleh
U955 - IMRB, Inserm, UPEC, Ecole Nationale Vétérinaire d’Alfort, Créteil, France (M.P., B.G., D.M.);Université Paris-Est, UMR S955, UPEC, Créteil, France (A.A.B., I.R., J.M.P.); INSERM U955, Team « Viruses, Hepatology, Cancer », Hôpital Henri Mondor, Créteil, France (A.A.B., J.M.P., I.R.); Centre de Biochimie Structurale (CBS), INSERM U1054, CNRS UMR5048, Université de Montpellier, Montpellier, France (J.F.G.); and Department of Virology, Hôpital Henri Mondor, Créteil, France (J.M.P.)
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Didier Morin
U955 - IMRB, Inserm, UPEC, Ecole Nationale Vétérinaire d’Alfort, Créteil, France (M.P., B.G., D.M.);Université Paris-Est, UMR S955, UPEC, Créteil, France (A.A.B., I.R., J.M.P.); INSERM U955, Team « Viruses, Hepatology, Cancer », Hôpital Henri Mondor, Créteil, France (A.A.B., J.M.P., I.R.); Centre de Biochimie Structurale (CBS), INSERM U1054, CNRS UMR5048, Université de Montpellier, Montpellier, France (J.F.G.); and Department of Virology, Hôpital Henri Mondor, Créteil, France (J.M.P.)
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Abstract

Mitochondrial permeability transition pore (mPTP) opening is a key event in cell death during myocardial ischemia reperfusion. Inhibition of its modulator cyclophilin D (CypD) by cyclosporine A (CsA) reduces ischemia-reperfusion injury. The use of cyclosporine A in this indication is debated; however, targeting mPTP remains a major goal to achieve. We investigated the protective effects of a new original small-molecule cyclophilin inhibitor C31, which was specifically designed to target CypD. CypD peptidylprolyl cis-trans isomerase (PPIase) activity was assessed by the standard chemotrypsin-coupled assay. The effects of C31 on mPTP opening were investigated in isolated mouse cardiac mitochondria by measuring mitochondrial swelling and calcium retention capacity (CRC) in rat H9C2 cardiomyoblasts and in adult mouse cardiomyocytes by fluorescence microscopy in isolated perfused mouse hearts and ex vivo after drug infusion in mice. C31 potently inhibited CypD PPIase activity and mitochondrial swelling. C31 was more effective at increasing mitochondrial CRC than CsA and was still able to increase CRC in Ppif−/− (CypD-inactivated) cardiac mitochondria. C31 delayed both mPTP opening and cell death in cardiomyocytes subjected to hypoxia reoxygenation. However, high concentrations of both drugs were necessary to reduce mPTP opening in isolated perfused hearts, and neither CsA nor C31 inhibited mPTP opening in heart after in vivo infusion, underlying the importance of myocardial drug distribution for cardioprotection. C31 is an original inhibitor of mPTP opening involving both CypD-dependent and -independent mechanisms. It constitutes a promising new cytoprotective agent. Optimization of its pharmacokinetic properties is now required prior to its use against cardiac ischemia-reperfusion injury.

SIGNIFICANCE STATEMENT This study demonstrates that the new cyclophilin inhibitor C31 potently inhibits cardiac mitochondrial permeability transition pore (mPTP) opening in vitro and ex vivo. The dual mechanism of action of C31 allows the prevention of mPTP opening beyond cyclophilin D inhibition. Further development of the compound might bring promising drug candidates for cardioprotection. However, the lack of effect of both C31 and cyclosporine A after systemic administration demonstrates the difficulties of targeting myocardial mitochondria in vivo and should be taken into account in cardioprotective strategies.

Footnotes

    • Received September 30, 2020.
    • Accepted December 8, 2020.
  • This work was supported by the French Ministry for Higher Education and Research (N° 2014-140 to M.P.) and The National Agency for Research on AIDS and Viral Hepatitis (to I.R.).

  • Conflict of interests: Inserm Transfert is the owner of patent EP 09306294.1 covering the family of cyclophilin inhibitors, including the C31 compound, for which A.A.-B., J.-F.G. and J.-M.P. are inventors. All other authors declare no competing financial interests.

  • https://doi.org/10.1124/jpet.120.000359.

  • Copyright © 2021 by The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 376 (3)
Journal of Pharmacology and Experimental Therapeutics
Vol. 376, Issue 3
1 Mar 2021
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Research ArticleCardiovascular

A Novel Inhibitor of Myocardial mPTP

Mathieu Panel, Abdelhakim Ahmed-Belkacem, Isaac Ruiz, Jean-François Guichou, Jean-Michel Pawlotsky, Bijan Ghaleh and Didier Morin
Journal of Pharmacology and Experimental Therapeutics March 1, 2021, 376 (3) 348-357; DOI: https://doi.org/10.1124/jpet.120.000359

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Research ArticleCardiovascular

A Novel Inhibitor of Myocardial mPTP

Mathieu Panel, Abdelhakim Ahmed-Belkacem, Isaac Ruiz, Jean-François Guichou, Jean-Michel Pawlotsky, Bijan Ghaleh and Didier Morin
Journal of Pharmacology and Experimental Therapeutics March 1, 2021, 376 (3) 348-357; DOI: https://doi.org/10.1124/jpet.120.000359
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