Τίτλος:
Nitroglycerine limits infarct size through S-nitrosation of cyclophilin D: A novel mechanism for an old drug
Γλώσσες Τεκμηρίου:
Αγγλικά
Περίληψη:
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. © The Author(s) 2018.
Συγγραφείς:
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.
Περιοδικό:
Cardiovascular Research
Εκδότης:
Oxford University Press
Λέξεις-κλειδιά:
arginine; citrulline; cyclophilin D; dimer; endothelial nitric oxide synthase; glyceryl trinitrate; nitric oxide; nitrite; cyclophilin; endothelial nitric oxide synthase; enzyme inhibitor; glyceryl trinitrate; nitric oxide donor; NOS3 protein, human; Nos3 protein, mouse; PPID protein, human, acute heart infarction; adult; aged; animal experiment; animal model; animal tissue; Article; clinical article; cohort analysis; controlled study; dimerization; drug mechanism; endothelial dysfunction; enzyme activity; female; heart infarction size; heart muscle ischemia; heart muscle necrosis; heart protection; hemodynamic parameters; human; human tissue; in vivo study; low drug dose; male; mouse; nitrosation; nonhuman; priority journal; reperfusion; ST segment elevation myocardial infarction; animal; apolipoprotein E knockout mouse; C57BL mouse; cardiac muscle cell; disease model; drug effect; enzymology; genetics; heart infarction; metabolism; middle aged; myocardial ischemia reperfusion injury; necrosis; nitrosation; pathology; signal transduction, Adult; Aged; Animals; Cyclophilins; Disease Models, Animal; Enzyme Inhibitors; Female; Humans; Male; Mice, Inbred C57BL; Mice, Knockout, ApoE; Middle Aged; Myocardial Infarction; Myocardial Reperfusion Injury; Myocytes, Cardiac; Necrosis; Nitric Oxide Donors; Nitric Oxide Synthase Type III; Nitroglycerin; Nitrosation; Signal Transduction
