A novel class of cardioprotective small-molecule PTP inhibitors
The result's identifiers
Result code in IS VaVaI
<a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F67985823%3A_____%2F20%3A00524241" target="_blank" >RIV/67985823:_____/20:00524241 - isvavai.cz</a>
Result on the web
<a href="https://doi.org/10.1016/j.phrs.2019.104548" target="_blank" >https://doi.org/10.1016/j.phrs.2019.104548</a>
DOI - Digital Object Identifier
<a href="http://dx.doi.org/10.1016/j.phrs.2019.104548" target="_blank" >10.1016/j.phrs.2019.104548</a>
Alternative languages
Result language
angličtina
Original language name
A novel class of cardioprotective small-molecule PTP inhibitors
Original language description
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.
Czech name
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Czech description
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Classification
Type
J<sub>imp</sub> - Article in a specialist periodical, which is included in the Web of Science database
CEP classification
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OECD FORD branch
30201 - Cardiac and Cardiovascular systems
Result continuities
Project
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Continuities
I - Institucionalni podpora na dlouhodoby koncepcni rozvoj vyzkumne organizace
Others
Publication year
2020
Confidentiality
S - Úplné a pravdivé údaje o projektu nepodléhají ochraně podle zvláštních právních předpisů
Data specific for result type
Name of the periodical
Pharmacological Research
ISSN
1043-6618
e-ISSN
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Volume of the periodical
151
Issue of the periodical within the volume
Jan
Country of publishing house
GB - UNITED KINGDOM
Number of pages
12
Pages from-to
104548
UT code for WoS article
000527002000005
EID of the result in the Scopus database
2-s2.0-85075501209