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

Sofia Iris Bibli, Andreas Papapetropoulos, Efstathios K. Iliodromitis, Andreas Daiber, Voahanginirina Randriamboavonjy, Sebastian Steven, Peter Brouckaert, Athanasia Chatzianastasiou, Kyriakos E. Kypreos, Derek J. Hausenloy, Ingrid Fleming, Ioanna Andreadou

Research output: Contribution to journalArticle

10 Scopus citations

Abstract

Aims 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. Methods and results 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. Conclusion 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.

Original languageEnglish (US)
Pages (from-to)625-636
Number of pages12
JournalCardiovascular research
Volume115
Issue number3
DOIs
StatePublished - Mar 1 2019
Externally publishedYes

Keywords

  • Cardioprotection
  • CypD nitros(yl)ation
  • eNOS
  • Nitroglycerine

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine
  • Physiology (medical)

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    Bibli, S. I., Papapetropoulos, A., Iliodromitis, E. K., Daiber, A., Randriamboavonjy, V., Steven, S., Brouckaert, P., Chatzianastasiou, A., Kypreos, K. E., Hausenloy, D. J., Fleming, I., & Andreadou, I. (2019). Nitroglycerine limits infarct size through S-nitrosation of cyclophilin D: A novel mechanism for an old drug. Cardiovascular research, 115(3), 625-636. https://doi.org/10.1093/cvr/cvy222