title: Cardioprotection by H2S Donors: Nitric Oxide-Dependent and ‑Independent Mechanisms.
abstract: Hydrogen sulfide (H2S) is a signaling molecule with protective effects in the cardiovascular system. To harness the therapeutic potential of H2S, a number of donors have been developed. The present study compares the cardioprotective actions of representative H2S donors from different classes and studies their mechanisms of action in myocardial injury in vitro and in vivo. Exposure of cardiomyocytes to H2O2 led to significant cytotoxicity, which was inhibited by sodium sulfide (Na2S), thiovaline (TV), GYY4137 [morpholin-4-ium 4 methoxyphenyl(morpholino) phosphinodithioate], and AP39 [(10-oxo-10-(4-(3-thioxo-3H-1,2-dithiol5yl)phenoxy)decyl) triphenylphospho-nium bromide]. Inhibition of nitric oxide (NO) synthesis prevented the cytoprotective effects of Na2S and TV, but not GYY4137 and AP39, against H2O2-induced cardiomyocyte injury. Mice subjected to left anterior descending coronary ligation were protected from ischemia-reperfusion injury by the H2S donors tested. Inhibition of nitric oxide synthase (NOS) in vivo blocked only the beneficial effect of Na2S. Moreover, Na2S, but not AP39, administration enhanced the phosphorylation of endothelial NOS and vasodilator-associated phosphoprotein. Both Na2S and AP39 reduced infarct size in mice lacking cyclophilin-D (CypD), a modulator of the mitochondrial permeability transition pore (PTP). Nevertheless, only AP39 displayed a direct effect on mitochondria by increasing the mitochondrial Ca(2+) retention capacity, which is evidence of decreased propensity to undergo permeability transition. We conclude that although all the H2S donors we tested limited infarct size, the pathways involved were not conserved. Na2S had no direct effects on PTP opening, and its action was nitric oxide dependent. In contrast, the cardioprotection exhibited by AP39 could result from a direct inhibitory effect on PTP acting at a site different than CypD.
authors.affiliation: George P. Livanos and Marianthi Simou Laboratories, First Department of Pulmonary and Critical Care Medicine, Evangelismos Hospital, Faculty of Medicine, National and Kapodistrian University of Athens, Athens, Greece (A.C., A.P.); Laboratory of Pharmacology, Democritus University of Thrace Medical School, Alexandroupolis, Greece (A.C., V.G.M.); Laboratory of Pharmacology, Faculty of Pharmacy, National and Kapodistrian University of Athens, Greece (S.-I.B., I.A., P.E., A.P.); Neuroscience Institute, CNR, Italy (N.K., F.D.L.); Biosciences, College of Life and Environmental Sciences, University of Exeter, Exeter, United Kingdom (M.E.W.); University of Exeter Medical School, Exeter, United Kingdom (M.W.); Department of Biomedical Sciences, University of Padova, Padova, Italy (F.D.L.); Center of Cardiology and Center for Thrombosis and Hemostasis, Medical Center of the Johannes Gutenberg University, Mainz, Germany (A.D.); Department of Anesthesiology, University of Texas Medical Branch, Galveston, Texas (C.S.); Center of Clinical, Experimental Surgery & Translational Research, Biomedical Research Foundation of the Academy of Athens, Athens, Greece (A.P.).
authors.forename: Athanasia
authors.initials: A
authors.lastname: Chatzianastasiou
authors.affiliation: George P. Livanos and Marianthi Simou Laboratories, First Department of Pulmonary and Critical Care Medicine, Evangelismos Hospital, Faculty of Medicine, National and Kapodistrian University of Athens, Athens, Greece (A.C., A.P.); Laboratory of Pharmacology, Democritus University of Thrace Medical School, Alexandroupolis, Greece (A.C., V.G.M.); Laboratory of Pharmacology, Faculty of Pharmacy, National and Kapodistrian University of Athens, Greece (S.-I.B., I.A., P.E., A.P.); Neuroscience Institute, CNR, Italy (N.K., F.D.L.); Biosciences, College of Life and Environmental Sciences, University of Exeter, Exeter, United Kingdom (M.E.W.); University of Exeter Medical School, Exeter, United Kingdom (M.W.); Department of Biomedical Sciences, University of Padova, Padova, Italy (F.D.L.); Center of Cardiology and Center for Thrombosis and Hemostasis, Medical Center of the Johannes Gutenberg University, Mainz, Germany (A.D.); Department of Anesthesiology, University of Texas Medical Branch, Galveston, Texas (C.S.); Center of Clinical, Experimental Surgery & Translational Research, Biomedical Research Foundation of the Academy of Athens, Athens, Greece (A.P.).
authors.forename: Sofia-Iris
authors.initials: SI
authors.lastname: Bibli
authors.affiliation: George P. Livanos and Marianthi Simou Laboratories, First Department of Pulmonary and Critical Care Medicine, Evangelismos Hospital, Faculty of Medicine, National and Kapodistrian University of Athens, Athens, Greece (A.C., A.P.); Laboratory of Pharmacology, Democritus University of Thrace Medical School, Alexandroupolis, Greece (A.C., V.G.M.); Laboratory of Pharmacology, Faculty of Pharmacy, National and Kapodistrian University of Athens, Greece (S.-I.B., I.A., P.E., A.P.); Neuroscience Institute, CNR, Italy (N.K., F.D.L.); Biosciences, College of Life and Environmental Sciences, University of Exeter, Exeter, United Kingdom (M.E.W.); University of Exeter Medical School, Exeter, United Kingdom (M.W.); Department of Biomedical Sciences, University of Padova, Padova, Italy (F.D.L.); Center of Cardiology and Center for Thrombosis and Hemostasis, Medical Center of the Johannes Gutenberg University, Mainz, Germany (A.D.); Department of Anesthesiology, University of Texas Medical Branch, Galveston, Texas (C.S.); Center of Clinical, Experimental Surgery & Translational Research, Biomedical Research Foundation of the Academy of Athens, Athens, Greece (A.P.).
authors.forename: Ioanna
authors.initials: I
authors.lastname: Andreadou
authors.affiliation: George P. Livanos and Marianthi Simou Laboratories, First Department of Pulmonary and Critical Care Medicine, Evangelismos Hospital, Faculty of Medicine, National and Kapodistrian University of Athens, Athens, Greece (A.C., A.P.); Laboratory of Pharmacology, Democritus University of Thrace Medical School, Alexandroupolis, Greece (A.C., V.G.M.); Laboratory of Pharmacology, Faculty of Pharmacy, National and Kapodistrian University of Athens, Greece (S.-I.B., I.A., P.E., A.P.); Neuroscience Institute, CNR, Italy (N.K., F.D.L.); Biosciences, College of Life and Environmental Sciences, University of Exeter, Exeter, United Kingdom (M.E.W.); University of Exeter Medical School, Exeter, United Kingdom (M.W.); Department of Biomedical Sciences, University of Padova, Padova, Italy (F.D.L.); Center of Cardiology and Center for Thrombosis and Hemostasis, Medical Center of the Johannes Gutenberg University, Mainz, Germany (A.D.); Department of Anesthesiology, University of Texas Medical Branch, Galveston, Texas (C.S.); Center of Clinical, Experimental Surgery & Translational Research, Biomedical Research Foundation of the Academy of Athens, Athens, Greece (A.P.).
authors.forename: Panagiotis
authors.initials: P
authors.lastname: Efentakis
authors.affiliation: George P. Livanos and Marianthi Simou Laboratories, First Department of Pulmonary and Critical Care Medicine, Evangelismos Hospital, Faculty of Medicine, National and Kapodistrian University of Athens, Athens, Greece (A.C., A.P.); Laboratory of Pharmacology, Democritus University of Thrace Medical School, Alexandroupolis, Greece (A.C., V.G.M.); Laboratory of Pharmacology, Faculty of Pharmacy, National and Kapodistrian University of Athens, Greece (S.-I.B., I.A., P.E., A.P.); Neuroscience Institute, CNR, Italy (N.K., F.D.L.); Biosciences, College of Life and Environmental Sciences, University of Exeter, Exeter, United Kingdom (M.E.W.); University of Exeter Medical School, Exeter, United Kingdom (M.W.); Department of Biomedical Sciences, University of Padova, Padova, Italy (F.D.L.); Center of Cardiology and Center for Thrombosis and Hemostasis, Medical Center of the Johannes Gutenberg University, Mainz, Germany (A.D.); Department of Anesthesiology, University of Texas Medical Branch, Galveston, Texas (C.S.); Center of Clinical, Experimental Surgery & Translational Research, Biomedical Research Foundation of the Academy of Athens, Athens, Greece (A.P.).
authors.forename: Nina
authors.initials: N
authors.lastname: Kaludercic
authors.affiliation: George P. Livanos and Marianthi Simou Laboratories, First Department of Pulmonary and Critical Care Medicine, Evangelismos Hospital, Faculty of Medicine, National and Kapodistrian University of Athens, Athens, Greece (A.C., A.P.); Laboratory of Pharmacology, Democritus University of Thrace Medical School, Alexandroupolis, Greece (A.C., V.G.M.); Laboratory of Pharmacology, Faculty of Pharmacy, National and Kapodistrian University of Athens, Greece (S.-I.B., I.A., P.E., A.P.); Neuroscience Institute, CNR, Italy (N.K., F.D.L.); Biosciences, College of Life and Environmental Sciences, University of Exeter, Exeter, United Kingdom (M.E.W.); University of Exeter Medical School, Exeter, United Kingdom (M.W.); Department of Biomedical Sciences, University of Padova, Padova, Italy (F.D.L.); Center of Cardiology and Center for Thrombosis and Hemostasis, Medical Center of the Johannes Gutenberg University, Mainz, Germany (A.D.); Department of Anesthesiology, University of Texas Medical Branch, Galveston, Texas (C.S.); Center of Clinical, Experimental Surgery & Translational Research, Biomedical Research Foundation of the Academy of Athens, Athens, Greece (A.P.).
authors.forename: Mark E
authors.initials: ME
authors.lastname: Wood
authors.affiliation: George P. Livanos and Marianthi Simou Laboratories, First Department of Pulmonary and Critical Care Medicine, Evangelismos Hospital, Faculty of Medicine, National and Kapodistrian University of Athens, Athens, Greece (A.C., A.P.); Laboratory of Pharmacology, Democritus University of Thrace Medical School, Alexandroupolis, Greece (A.C., V.G.M.); Laboratory of Pharmacology, Faculty of Pharmacy, National and Kapodistrian University of Athens, Greece (S.-I.B., I.A., P.E., A.P.); Neuroscience Institute, CNR, Italy (N.K., F.D.L.); Biosciences, College of Life and Environmental Sciences, University of Exeter, Exeter, United Kingdom (M.E.W.); University of Exeter Medical School, Exeter, United Kingdom (M.W.); Department of Biomedical Sciences, University of Padova, Padova, Italy (F.D.L.); Center of Cardiology and Center for Thrombosis and Hemostasis, Medical Center of the Johannes Gutenberg University, Mainz, Germany (A.D.); Department of Anesthesiology, University of Texas Medical Branch, Galveston, Texas (C.S.); Center of Clinical, Experimental Surgery & Translational Research, Biomedical Research Foundation of the Academy of Athens, Athens, Greece (A.P.).
authors.forename: Matthew
authors.initials: M
authors.lastname: Whiteman
authors.affiliation: George P. Livanos and Marianthi Simou Laboratories, First Department of Pulmonary and Critical Care Medicine, Evangelismos Hospital, Faculty of Medicine, National and Kapodistrian University of Athens, Athens, Greece (A.C., A.P.); Laboratory of Pharmacology, Democritus University of Thrace Medical School, Alexandroupolis, Greece (A.C., V.G.M.); Laboratory of Pharmacology, Faculty of Pharmacy, National and Kapodistrian University of Athens, Greece (S.-I.B., I.A., P.E., A.P.); Neuroscience Institute, CNR, Italy (N.K., F.D.L.); Biosciences, College of Life and Environmental Sciences, University of Exeter, Exeter, United Kingdom (M.E.W.); University of Exeter Medical School, Exeter, United Kingdom (M.W.); Department of Biomedical Sciences, University of Padova, Padova, Italy (F.D.L.); Center of Cardiology and Center for Thrombosis and Hemostasis, Medical Center of the Johannes Gutenberg University, Mainz, Germany (A.D.); Department of Anesthesiology, University of Texas Medical Branch, Galveston, Texas (C.S.); Center of Clinical, Experimental Surgery & Translational Research, Biomedical Research Foundation of the Academy of Athens, Athens, Greece (A.P.).
authors.forename: Fabio
authors.initials: F
authors.lastname: Di Lisa
authors.affiliation: George P. Livanos and Marianthi Simou Laboratories, First Department of Pulmonary and Critical Care Medicine, Evangelismos Hospital, Faculty of Medicine, National and Kapodistrian University of Athens, Athens, Greece (A.C., A.P.); Laboratory of Pharmacology, Democritus University of Thrace Medical School, Alexandroupolis, Greece (A.C., V.G.M.); Laboratory of Pharmacology, Faculty of Pharmacy, National and Kapodistrian University of Athens, Greece (S.-I.B., I.A., P.E., A.P.); Neuroscience Institute, CNR, Italy (N.K., F.D.L.); Biosciences, College of Life and Environmental Sciences, University of Exeter, Exeter, United Kingdom (M.E.W.); University of Exeter Medical School, Exeter, United Kingdom (M.W.); Department of Biomedical Sciences, University of Padova, Padova, Italy (F.D.L.); Center of Cardiology and Center for Thrombosis and Hemostasis, Medical Center of the Johannes Gutenberg University, Mainz, Germany (A.D.); Department of Anesthesiology, University of Texas Medical Branch, Galveston, Texas (C.S.); Center of Clinical, Experimental Surgery & Translational Research, Biomedical Research Foundation of the Academy of Athens, Athens, Greece (A.P.).
authors.forename: Andreas
authors.initials: A
authors.lastname: Daiber
authors.affiliation: George P. Livanos and Marianthi Simou Laboratories, First Department of Pulmonary and Critical Care Medicine, Evangelismos Hospital, Faculty of Medicine, National and Kapodistrian University of Athens, Athens, Greece (A.C., A.P.); Laboratory of Pharmacology, Democritus University of Thrace Medical School, Alexandroupolis, Greece (A.C., V.G.M.); Laboratory of Pharmacology, Faculty of Pharmacy, National and Kapodistrian University of Athens, Greece (S.-I.B., I.A., P.E., A.P.); Neuroscience Institute, CNR, Italy (N.K., F.D.L.); Biosciences, College of Life and Environmental Sciences, University of Exeter, Exeter, United Kingdom (M.E.W.); University of Exeter Medical School, Exeter, United Kingdom (M.W.); Department of Biomedical Sciences, University of Padova, Padova, Italy (F.D.L.); Center of Cardiology and Center for Thrombosis and Hemostasis, Medical Center of the Johannes Gutenberg University, Mainz, Germany (A.D.); Department of Anesthesiology, University of Texas Medical Branch, Galveston, Texas (C.S.); Center of Clinical, Experimental Surgery & Translational Research, Biomedical Research Foundation of the Academy of Athens, Athens, Greece (A.P.).
authors.forename: Vangelis G
authors.initials: VG
authors.lastname: Manolopoulos
authors.affiliation: George P. Livanos and Marianthi Simou Laboratories, First Department of Pulmonary and Critical Care Medicine, Evangelismos Hospital, Faculty of Medicine, National and Kapodistrian University of Athens, Athens, Greece (A.C., A.P.); Laboratory of Pharmacology, Democritus University of Thrace Medical School, Alexandroupolis, Greece (A.C., V.G.M.); Laboratory of Pharmacology, Faculty of Pharmacy, National and Kapodistrian University of Athens, Greece (S.-I.B., I.A., P.E., A.P.); Neuroscience Institute, CNR, Italy (N.K., F.D.L.); Biosciences, College of Life and Environmental Sciences, University of Exeter, Exeter, United Kingdom (M.E.W.); University of Exeter Medical School, Exeter, United Kingdom (M.W.); Department of Biomedical Sciences, University of Padova, Padova, Italy (F.D.L.); Center of Cardiology and Center for Thrombosis and Hemostasis, Medical Center of the Johannes Gutenberg University, Mainz, Germany (A.D.); Department of Anesthesiology, University of Texas Medical Branch, Galveston, Texas (C.S.); Center of Clinical, Experimental Surgery & Translational Research, Biomedical Research Foundation of the Academy of Athens, Athens, Greece (A.P.).
authors.forename: Csaba
authors.initials: C
authors.lastname: Szabó
authors.affiliation: George P. Livanos and Marianthi Simou Laboratories, First Department of Pulmonary and Critical Care Medicine, Evangelismos Hospital, Faculty of Medicine, National and Kapodistrian University of Athens, Athens, Greece (A.C., A.P.); Laboratory of Pharmacology, Democritus University of Thrace Medical School, Alexandroupolis, Greece (A.C., V.G.M.); Laboratory of Pharmacology, Faculty of Pharmacy, National and Kapodistrian University of Athens, Greece (S.-I.B., I.A., P.E., A.P.); Neuroscience Institute, CNR, Italy (N.K., F.D.L.); Biosciences, College of Life and Environmental Sciences, University of Exeter, Exeter, United Kingdom (M.E.W.); University of Exeter Medical School, Exeter, United Kingdom (M.W.); Department of Biomedical Sciences, University of Padova, Padova, Italy (F.D.L.); Center of Cardiology and Center for Thrombosis and Hemostasis, Medical Center of the Johannes Gutenberg University, Mainz, Germany (A.D.); Department of Anesthesiology, University of Texas Medical Branch, Galveston, Texas (C.S.); Center of Clinical, Experimental Surgery & Translational Research, Biomedical Research Foundation of the Academy of Athens, Athens, Greece (A.P.) apapapet@pharm.uoa.gr.
authors.forename: Andreas
authors.initials: A
authors.lastname: Papapetropoulos
mesh_terms: D000818:Animals; D002316:Cardiotonic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D002460:Cell Line; D006801:Humans; D006862:Hydrogen Sulfide / Q000378:metabolism*; D008297:Male; D051379:Mice; D008929:Mitochondria, Heart / Q000187:drug effects / Q000378:metabolism; D015428:Myocardial Reperfusion Injury / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D009569:Nitric Oxide / Q000378:metabolism*
chemical_list: D002316:Cardiotonic Agents; D009569:Nitric Oxide; D006862:Hydrogen Sulfide