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

Author:

Bibli Sofia-Iris123,Papapetropoulos Andreas1,Iliodromitis Efstathios K4,Daiber Andreas35,Randriamboavonjy Voahanginirina23,Steven Sebastian56,Brouckaert Peter78,Chatzianastasiou Athanasia1,Kypreos Kyriakos E9,Hausenloy Derek J1011121314,Fleming Ingrid23,Andreadou Ioanna1

Affiliation:

1. Laboratoty of Pharmacology, Faculty of Pharmacy, National and Kapodistrian University of Athens, Panepistimiopolis, Zografou, Athens, Greece

2. Institute for Vascular Signaling, Goethe University, Theodor Stern Kai 7, Frankfurt, Germany

3. German Center for Cardiovascular Research (DZHK), Partner Site Rhine-Main, Mainz, Germany

4. Faculty of Medicine, Second Department of Cardiology, Attikon University Hospital, National and Kapodistrian University of Athens, Athens, Greece

5. University Medical Center of Mainz, Center for Cardiology, Cardiology I, Molecular Cardiology, Mainz, Germany

6. University Medical Center of Mainz, Center for Thrombosis and Hemostasis (CTH), Mainz, Germany

7. Department of Biomedical Molecular Biology, Ghent University, Ghent, Belgium

8. Department of Molecular Biomedical Research, VIB, Ghent, Belgium

9. Department of Pharmacology, University of Patras Medical School, Patras, Greece

10. Cardiovascular & Metabolic Disorders Program, Duke-National University of Singapore Medical School, Singapore

11. National Heart Research Institute Singapore, National Heart Centre, Singapore

12. Yong Loo Lin School of Medicine, National University 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

Abstract

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.

Funder

COST

ENOG

European network on gasotransmitters

COST Action

EU-CARDIOPROTECTION

COST-ACTION

European Society of Cardiology

Basic Research Fellowship 2016 and Research

Bodossaki Foundation

Mozamvinos Post-Doctoral Fellowship 2017

Schering Stiftung

Young Investigator Fund for Innovative Research 2017

Deutsche Forschungsgemeinschaft

Exzellenzcluster 147 ‘Cardio-Pulmonary Systems’

British Heart Foundation

National Institute for Health Research University College London Hospitals Biomedical Research Centre

Duke-National University Singapore Medical School

Singapore Ministry of Health’s National Medical Research Council

Clinician Scientist-Senior Investigator

NMRC

Collaborative Centre Grant

Singapore Ministry of Education Academic Research Fund Tier 2

Publisher

Oxford University Press (OUP)

Subject

Physiology (medical),Cardiology and Cardiovascular Medicine,Physiology

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