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A novel class of cardioprotective small-molecule PTP inhibitors
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SYSNO ASEP 0524241 Document Type J - Journal Article R&D Document Type Journal Article Subsidiary J Článek ve WOS Title A novel class of cardioprotective small-molecule PTP inhibitors Author(s) Antonucci, S. (IT)
Di Sante, M. (IT)
Sileikyte, J. (US)
Deveraux, J. (US)
Bauer, T. (US)
Bround, M. J. (US)
Menabo, R. (IT)
Paillard, M. (FR)
Alánová, Petra (FGU-C) RID, ORCID
Carraro, M. (IT)
Ovize, M. (FR)
Molkentin, J. D. (US)
Cohen, M. (US)
Forte, M. A. (US)
Bernardi, P. (IT)
Di Lisa, F. (IT)
Murphy, E. (US)Article number 104548 Source Title Pharmacological Research. - : Elsevier - ISSN 1043-6618
Roč. 151, Jan (2020)Number of pages 12 s. Language eng - English Country GB - United Kingdom Keywords permeability transition ; mitochondria ; cardiomyocytes ; cardioprotection ; ischemia ; reperfusion Subject RIV FA - Cardiovascular Diseases incl. Cardiotharic Surgery OECD category Cardiac and Cardiovascular systems Method of publishing Limited access Institutional support FGU-C - RVO:67985823 UT WOS 000527002000005 EID SCOPUS 85075501209 DOI 10.1016/j.phrs.2019.104548 Annotation 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. Workplace Institute of Physiology Contact Lucie Trajhanová, lucie.trajhanova@fgu.cas.cz, Tel.: 241 062 400 Year of Publishing 2021 Electronic address https://doi.org/10.1016/j.phrs.2019.104548
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