Sofia-Iris Bibli1, Ioanna Andreadou2, Athanasia Chatzianastasiou3, Christos Tzimas4, Despina Sanoudou5, Evangelia Kranias6, Peter Brouckaert7, Ciro Coletta8, Csaba Szabo8, Dimitrios Th Kremastinos9, Efstathios K Iliodromitis9, Andreas Papapetropoulos10. 1. Faculty of Pharmacy, University of Athens, Panepistimiopolis, Zografou, Athens 15771, Greece. 2. Faculty of Pharmacy, University of Athens, Panepistimiopolis, Zografou, Athens 15771, Greece jandread@pharm.uoa.gr apapapet@pharm.uoa.gr. 3. Faculty of Medicine, First Department of Critical Care and Pulmonary Services, Evangelismos Hospital, University of Athens, Athens, Greece. 4. Molecular Biology Department, Biomedical Research Foundation of the Academy of Athens, Athens, Greece. 5. Molecular Biology Department, Biomedical Research Foundation of the Academy of Athens, Athens, Greece Department of Pharmacology, Faculty of Medicine, University of Athens, Athens, Greece. 6. Molecular Biology Department, Biomedical Research Foundation of the Academy of Athens, Athens, Greece Department of Pharmacology and Cell Biophysics, College of Medicine, University of Cincinnati, Cincinnati, OH, USA. 7. Department of Biomedical Molecular Biology, Ghent University, Ghent, Belgium Department of Molecular Biomedical Research, VIB, Ghent, Belgium. 8. Department of Anesthesiology University of Texas Medical Branch, Galveston, TX, USA Shriners Burns Hospital for Children, Galveston, TX, USA. 9. Faculty of Medicine, Second Department of Cardiology, Attikon University Hospital, University of Athens, Athens, Greece. 10. Faculty of Pharmacy, University of Athens, Panepistimiopolis, Zografou, Athens 15771, Greece Molecular Biology Department, Biomedical Research Foundation of the Academy of Athens, Athens, Greece jandread@pharm.uoa.gr apapapet@pharm.uoa.gr.
Abstract
AIMS: H2S is known to confer cardioprotection; however, the pathways mediating its effects in vivo remain incompletely understood. The purpose of the present study is to evaluate the contribution of cGMP-regulated pathways in the infarct-limiting effect of H2S in vivo. METHODS AND RESULTS: Anaesthetized rabbits were subjected to myocardial ischaemia (I)/reperfusion (R), and infarct size was determined in control or H2S-exposed groups. The H2S donor sodium hydrosulfide (NaHS, an agent that generates H2S) increased cardiac cGMP and reduced the infarct size. The cGMP-dependent protein kinase (PKG)-I inhibitor DT2 abrogated the protective effect of NaHS, whereas the control peptide TAT or l-nitroarginine methyl ester (l-NAME) did not alter the effect of NaHS. Moreover, the KATP channel inhibitor, glibenclamide, partially reversed the effects of NaHS, whereas inhibition of mitochondrial KATP did not modify the NaHS response. NaHS enhanced phosphorylation of phospholamban (PLN), in a PKG-dependent manner. To further investigate the role of PLN in H2S-mediated cardioprotection, wild-type and PLN KO mice underwent I/R. NaHS did not exert cardioprotection in PLN KO mice. Unlike what was observed in rabbits, genetic or pharmacological inhibition of eNOS abolished the infarct-limiting effect of NaHS in mice. CONCLUSIONS: Our findings demonstrate (i) that administration of NaHS induces cardioprotection via a cGMP/PKG/PLN pathway and (ii) contribution of nitric oxide to the H2S response is species-specific. Published on behalf of the European Society of Cardiology. All rights reserved.
AIMS: H2S is known to confer cardioprotection; however, the pathways mediating its effects in vivo remain incompletely understood. The purpose of the present study is to evaluate the contribution of cGMP-regulated pathways in the infarct-limiting effect of H2S in vivo. METHODS AND RESULTS: Anaesthetized rabbits were subjected to myocardial ischaemia (I)/reperfusion (R), and infarct size was determined in control or H2S-exposed groups. The H2Sdonorsodium hydrosulfide (NaHS, an agent that generates H2S) increased cardiac cGMP and reduced the infarct size. The cGMP-dependent protein kinase (PKG)-I inhibitor DT2 abrogated the protective effect of NaHS, whereas the control peptide TAT or l-nitroarginine methyl ester (l-NAME) did not alter the effect of NaHS. Moreover, the KATP channel inhibitor, glibenclamide, partially reversed the effects of NaHS, whereas inhibition of mitochondrial KATP did not modify the NaHS response. NaHS enhanced phosphorylation of phospholamban (PLN), in a PKG-dependent manner. To further investigate the role of PLN in H2S-mediated cardioprotection, wild-type and PLN KO mice underwent I/R. NaHS did not exert cardioprotection in PLN KO mice. Unlike what was observed in rabbits, genetic or pharmacological inhibition of eNOS abolished the infarct-limiting effect of NaHS in mice. CONCLUSIONS: Our findings demonstrate (i) that administration of NaHS induces cardioprotection via a cGMP/PKG/PLN pathway and (ii) contribution of nitric oxide to the H2S response is species-specific. Published on behalf of the European Society of Cardiology. All rights reserved.
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