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Nitroglycerine limits infarct size through S-nitrosation of cyclophilin D: a novel mechanism for an old drug.

Authors
  • Bibli, Sofia-Iris1, 2, 3
  • Papapetropoulos, Andreas1
  • Iliodromitis, Efstathios K4
  • Daiber, Andreas3, 5
  • Randriamboavonjy, Voahanginirina2, 3
  • Steven, Sebastian5, 6
  • Brouckaert, Peter7, 8
  • Chatzianastasiou, Athanasia1
  • Kypreos, Kyriakos E9
  • Hausenloy, Derek J10, 11, 12, 13, 14, 15
  • Fleming, Ingrid2, 3
  • Andreadou, Ioanna1
  • 1 Laboratoty of Pharmacology, Faculty of Pharmacy, National and Kapodistrian University of Athens, Panepistimiopolis, Zografou, Athens, Greece. , (Greece)
  • 2 Institute for Vascular Signaling, Goethe University, Theodor Stern Kai 7, Frankfurt, Germany. , (Germany)
  • 3 German Center for Cardiovascular Research (DZHK), Partner Site Rhine-Main, Mainz, Germany. , (Germany)
  • 4 Faculty of Medicine, Second Department of Cardiology, Attikon University Hospital, National and Kapodistrian University of Athens, Athens, Greece. , (Greece)
  • 5 University Medical Center of Mainz, Center for Cardiology, Cardiology I, Molecular Cardiology, Mainz, Germany. , (Germany)
  • 6 University Medical Center of Mainz, Center for Thrombosis and Hemostasis (CTH), Mainz, Germany. , (Germany)
  • 7 Department of Biomedical Molecular Biology, Ghent University, Ghent, Belgium. , (Belgium)
  • 8 Department of Molecular Biomedical Research, VIB, Ghent, Belgium. , (Belgium)
  • 9 Department of Pharmacology, University of Patras Medical School, Patras, Greece. , (Greece)
  • 10 Cardiovascular & Metabolic Disorders Program, Duke-National University of Singapore Medical School, Singapore. , (Singapore)
  • 11 National Heart Research Institute Singapore, National Heart Centre, Singapore. , (Singapore)
  • 12 Yong Loo Lin School of Medicine, National University Singapore, Singapore. , (Singapore)
  • 13 The Hatter Cardiovascular Institute, University College London, London, UK.
  • 14 The National Institute of Health Research University College London Hospitals Biomedical Research Centre, Research & Development, London, UK.
  • 15 Department of Cardiology, Barts Heart Centre, St Bartholomew's Hospital, London, UK.
Type
Published Article
Journal
Cardiovascular Research
Publisher
Oxford University Press
Publication Date
Mar 01, 2019
Volume
115
Issue
3
Pages
625–636
Identifiers
DOI: 10.1093/cvr/cvy222
PMID: 30165375
Source
Medline
Keywords
Language
English
License
Unknown

Abstract

Nitroglycerine (NTG) given prior to an ischaemic insult exerts cardioprotective effects. However, whether administration of an acute low dose of NTG in a clinically relevant manner following an ischaemic episode limits infarct size, has not yet been explored. Adult mice were subjected to acute myocardial infarction in vivo and then treated with vehicle or low-dose NTG prior to reperfusion. This treatment regimen minimized myocardial infarct size without affecting haemodynamic parameters but the protective effect was absent in mice rendered tolerant to the drug. Mechanistically, NTG was shown to nitrosate and inhibit cyclophilin D (CypD), and NTG administration failed to limit infarct size in CypD knockout mice. Additional experiments revealed lack of the NTG protective effect following genetic (knockout mice) or pharmacological inhibition (L-NAME treatment) of the endothelial nitric oxide synthase (eNOS). The protective effect of NTG was attributed to preservation of the eNOS dimer. Moreover, NTG retained its cardioprotective effects in a model of endothelial dysfunction (ApoE knockout) by preserving CypD nitrosation. Human ischaemic heart biopsies revealed reduced eNOS activity and exhibited reduced CypD nitrosation. Low-dose NTG given prior to reperfusion reduces myocardial infarct size by preserving eNOS function, and the subsequent eNOS-dependent S-nitrosation of CypD, inhibiting cardiomyocyte necrosis. This novel pharmacological action of NTG warrants confirmation in clinical studies, although our data in human biopsies provide promising preliminary results. Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2018. For permissions, please email: [email protected]

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