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

(2019) CARDIOVASCULAR RESEARCH. 115(3). p.625-636
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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.
Keywords
NITRIC-OXIDE SYNTHASE, NITRATE THERAPY, MYOCARDIAL-INFARCTION, CARDIOPROTECTION, ACTIVATION, BLOOD, NITROSYLATION, TOLERANCE, ISCHEMIA, RELEASE, Nitroglycerine, Cardioprotection, eNOS, CypD nitros(yl)ation

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Citation

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Chicago
Bibli, Sofia-Iris, Andreas Papapetropoulos, Efstathios K Iliodromitis, Andreas Daiber, Voahanginirina Randriamboavonjy, Sebastian Steven, Peter Brouckaert, et al. 2019. “Nitroglycerine Limits Infarct Size Through S-nitrosation of Cyclophilin D : a Novel Mechanism for an Old Drug.” Cardiovascular Research 115 (3): 625–636.
APA
Bibli, S.-I., Papapetropoulos, A., Iliodromitis, E. K., Daiber, A., Randriamboavonjy, V., Steven, S., Brouckaert, P., et al. (2019). Nitroglycerine limits infarct size through S-nitrosation of cyclophilin D : a novel mechanism for an old drug. CARDIOVASCULAR RESEARCH, 115(3), 625–636.
Vancouver
1.
Bibli S-I, Papapetropoulos A, Iliodromitis EK, Daiber A, Randriamboavonjy V, Steven S, et al. Nitroglycerine limits infarct size through S-nitrosation of cyclophilin D : a novel mechanism for an old drug. CARDIOVASCULAR RESEARCH. 2019;115(3):625–36.
MLA
Bibli, Sofia-Iris et al. “Nitroglycerine Limits Infarct Size Through S-nitrosation of Cyclophilin D : a Novel Mechanism for an Old Drug.” CARDIOVASCULAR RESEARCH 115.3 (2019): 625–636. Print.
@article{8613554,
  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.},
  author       = {Bibli, Sofia-Iris and Papapetropoulos, Andreas and Iliodromitis, Efstathios K and Daiber, Andreas and Randriamboavonjy, Voahanginirina and Steven, Sebastian and Brouckaert, Peter and Chatzianastasiou, Athanasia and Kypreos, Kyriakos E and Hausenloy, Derek J and Fleming, Ingrid and Andreadou, Ioanna},
  issn         = {0008-6363},
  journal      = {CARDIOVASCULAR RESEARCH},
  keywords     = {NITRIC-OXIDE SYNTHASE,NITRATE THERAPY,MYOCARDIAL-INFARCTION,CARDIOPROTECTION,ACTIVATION,BLOOD,NITROSYLATION,TOLERANCE,ISCHEMIA,RELEASE,Nitroglycerine,Cardioprotection,eNOS,CypD nitros(yl)ation},
  language     = {eng},
  number       = {3},
  pages        = {625--636},
  title        = {Nitroglycerine limits infarct size through S-nitrosation of cyclophilin D : a novel mechanism for an old drug},
  url          = {http://dx.doi.org/10.1093/cvr/cvy222},
  volume       = {115},
  year         = {2019},
}

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