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A novel class of cardioprotective small-molecule PTP inhibitors

S. Antonucci, M. Di Sante, J. Sileikyte, J. Deveraux, T. Bauer, MJ. Bround, R. Menabò, M. Paillard, P. Alanova, M. Carraro, M. Ovize, JD. Molkentin, M. Cohen, MA. Forte, P. Bernardi, F. Di Lisa, E. Murphy

. 2020 ; 151 (-) : 104548. [pub] 20191120

Language English Country Netherlands

Document type Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't

Persistent link   https://www.medvik.cz/link/bmc21013002

Ischemia/reperfusion (I/R) injury is mediated in large part by opening of the mitochondrial permeability transition pore (PTP). Consequently, inhibitors of the PTP hold great promise for the treatment of a variety of cardiovascular disorders. At present, PTP inhibition is obtained only through the use of drugs (e.g. cyclosporine A, CsA) targeting cyclophilin D (CyPD) which is a key modulator, but not a structural component of the PTP. This limitation might explain controversial findings in clinical studies. Therefore, we investigated the protective effects against I/R injury of small-molecule inhibitors of the PTP (63 and TR002) that do not target CyPD. Both compounds exhibited a dose-dependent inhibition of PTP opening in isolated mitochondria and were more potent than CsA. Notably, PTP inhibition was observed also in mitochondria devoid of CyPD. Compounds 63 and TR002 prevented PTP opening and mitochondrial depolarization induced by Ca2+ overload and by reactive oxygen species in neonatal rat ventricular myocytes (NRVMs). Remarkably, both compounds prevented cell death, contractile dysfunction and sarcomeric derangement induced by anoxia/reoxygenation injury in NRVMs at sub-micromolar concentrations, and were more potent than CsA. Cardioprotection was observed also in adult mouse ventricular myocytes and human iPSc-derived cardiomyocytes, as well as ex vivo in perfused hearts. Thus, this study demonstrates that 63 and TR002 represent novel cardioprotective agents that inhibit PTP opening independent of CyPD targeting.

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$a Ischemia/reperfusion (I/R) injury is mediated in large part by opening of the mitochondrial permeability transition pore (PTP). Consequently, inhibitors of the PTP hold great promise for the treatment of a variety of cardiovascular disorders. At present, PTP inhibition is obtained only through the use of drugs (e.g. cyclosporine A, CsA) targeting cyclophilin D (CyPD) which is a key modulator, but not a structural component of the PTP. This limitation might explain controversial findings in clinical studies. Therefore, we investigated the protective effects against I/R injury of small-molecule inhibitors of the PTP (63 and TR002) that do not target CyPD. Both compounds exhibited a dose-dependent inhibition of PTP opening in isolated mitochondria and were more potent than CsA. Notably, PTP inhibition was observed also in mitochondria devoid of CyPD. Compounds 63 and TR002 prevented PTP opening and mitochondrial depolarization induced by Ca2+ overload and by reactive oxygen species in neonatal rat ventricular myocytes (NRVMs). Remarkably, both compounds prevented cell death, contractile dysfunction and sarcomeric derangement induced by anoxia/reoxygenation injury in NRVMs at sub-micromolar concentrations, and were more potent than CsA. Cardioprotection was observed also in adult mouse ventricular myocytes and human iPSc-derived cardiomyocytes, as well as ex vivo in perfused hearts. Thus, this study demonstrates that 63 and TR002 represent novel cardioprotective agents that inhibit PTP opening independent of CyPD targeting.
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$a Di Sante, Moises $u Department of Biomedical Sciences, University of Padova, Padova, Italy
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$a Sileikyte, Justina $u Vollum Institute, and Department of Physiology and Pharmacology, Portland, OR, USA
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$a Deveraux, Jordan $u Vollum Institute, and Department of Physiology and Pharmacology, Portland, OR, USA
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$a Alanova, Petra $u Department of Biomedical Sciences, University of Padova, Padova, Italy; Department of Developmental Cardiology, Institute of Physiology CAS, Prague, Czech Republic
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$a Carraro, Michela $u Department of Biomedical Sciences, University of Padova, Padova, Italy
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$a Ovize, Michel $u CarMeN Laboratory, University Claude Bernard Lyon 1, INSA Lyon, Oullins, France
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$a Cohen, Michael $u Vollum Institute, and Department of Physiology and Pharmacology, Portland, OR, USA
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$a Forte, Michael A $u Vollum Institute, and Department of Physiology and Pharmacology, Portland, OR, USA
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$a Bernardi, Paolo $u Department of Biomedical Sciences, University of Padova, Padova, Italy; National Research Council of Italy (CNR), Padova, Italy
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$a Di Lisa, Fabio $u Department of Biomedical Sciences, University of Padova, Padova, Italy; National Research Council of Italy (CNR), Padova, Italy. Electronic address: dilisa@bio.unipd.it
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$a Murphy, Elizabeth $u Systems Biology Center, NHLBI, NIH, Bethesda, MD, USA. Electronic address: murphy1@nhlbi.nih.gov
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