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

Bibli, S-I; Papapetropoulos, A; Iliodromitis, EK; Daiber, A; Randriamboavonjy, V; Steven, S; Brouckaert, P; ... Andreadou, I; + view all (2019) Nitroglycerine limits infarct size through S-nitrosation of cyclophilin D: a novel mechanism for an old drug. Cardiovascular Research , 115 (3) pp. 625-636. 10.1093/cvr/cvy222. Green open access

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Abstract

Aims: Nitroglycerin (NTG) given prior to an ischemic insult exerts cardioprotective effects. However, whether administration of an acute low dose of NTG in a clinically relevant manner following an ischemic 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 hemodynamic 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 ischemic heart biopsies revealed reduced eNOS activity and exhibited reduced CypD nitrosation. Conclusions: Low dose NTG given prior to reperfusion reduces myocardial infarct size by preserving eNOS function, and the subsequent eNOS-dependent S-nitrosation of cyclophilin D, inhibiting cardiomyocyte necrosis. This novel pharmacological action of NTG warrants confirmation in clinical studies, although our data in human biopsies provide promising preliminary results.

Type: Article
Title: Nitroglycerine limits infarct size through S-nitrosation of cyclophilin D: a novel mechanism for an old drug
Location: England
Open access status: An open access version is available from UCL Discovery
DOI: 10.1093/cvr/cvy222
Publisher version: https://doi.org/10.1093/cvr/cvy222
Language: English
Additional information: This version is the author accepted manuscript. For information on re-use, please refer to the publisher’s terms and conditions.
Keywords: Nitroglycerine , Cardioprotection , eNOS, CypD, nitros(yl)ation
UCL classification: UCL > Provost and Vice Provost Offices
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Pop Health Sciences > Institute of Cardiovascular Science
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Pop Health Sciences > Institute of Cardiovascular Science > Pre-clinical and Fundamental Science
URI: https://discovery.ucl.ac.uk/id/eprint/10055672
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