TY - JOUR
T1 - A novel class of cardioprotective small-molecule PTP inhibitors
AU - Antonucci, Salvatore
AU - Di Sante, Moises
AU - Sileikyte, Justina
AU - Deveraux, Jordan
AU - Bauer, Tyler
AU - Bround, Michael J.
AU - Menabò, Roberta
AU - Paillard, Melanie
AU - Alanova, Petra
AU - Carraro, Michela
AU - Ovize, Michel
AU - Molkentin, Jeffery D.
AU - Cohen, Michael
AU - Forte, Michael A.
AU - Bernardi, Paolo
AU - Di Lisa, Fabio
AU - Murphy, Elizabeth
N1 - Funding Information:
This work was supported by the Leducq Transatlantic Network of Excellence 16CVD04, the COST Action EU-CARDIOPROTECTION CA16225, the Grant number MSM200111701 provided by the Czech Academy of Sciences. TMB was supported by the NIH Medical Research Scholars Program, a public-private partnership supported jointly by the NIH and contributions to the Foundation for the NIH from the Doris Duke Charitable Foundation, the American Association for Dental Research, the Colgate-Palmolive Company, and other private donors.
Funding Information:
This work was supported by the Leducq Transatlantic Network of Excellence 16CVD04, the COST Action EU-CARDIOPROTECTION CA16225, the Grant number MSM200111701 provided by the Czech Academy of Sciences . TMB was supported by the NIH Medical Research Scholars Program , a public-private partnership supported jointly by the NIH and contributions to the Foundation for the NIH from the Doris Duke Charitable Foundation , the American Association for Dental Research , the Colgate-Palmolive Company , and other private donors.
Publisher Copyright:
© 2019
PY - 2020/1
Y1 - 2020/1
N2 - 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.
AB - 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.
KW - Caffeine (PubChem CID: 2519)
KW - Calcimycin (PubChem CID: 40486)
KW - Cardiomyocytes
KW - Cardioprotection
KW - Compound 63 (PubChem CID: 75204518)
KW - Cyclosporine A (PubChem CID: 5284373)
KW - Ischemia
KW - MitoParaquat (PubChem CID: 129909777)
KW - Mitochondria
KW - Permeability transition
KW - Reperfusion
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UR - http://www.scopus.com/inward/citedby.url?scp=85075501209&partnerID=8YFLogxK
U2 - 10.1016/j.phrs.2019.104548
DO - 10.1016/j.phrs.2019.104548
M3 - Article
C2 - 31759087
AN - SCOPUS:85075501209
SN - 1043-6618
VL - 151
JO - Pharmacological Research
JF - Pharmacological Research
M1 - 104548
ER -