Τίτλος:
Cardioprotection by H2S Donors: Nitric Oxide-Dependent and -Independent Mechanisms
Γλώσσες Τεκμηρίου:
Αγγλικά
Περίληψη:
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 inmyocardial 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 Ca2+ 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. Copyright © 2016 by The American Society for Pharmacology and Experimental Therapeutics.
Συγγραφείς:
Chatzianastasiou, A.
Bibli, S.-I.
Andreadou, I.
Efentakis, P.
Kaludercic, N.
Wood, M.E.
Whiteman, M.
Lisa, F.D.
Daiber, A.
Manolopoulos, V.G.
Szabó, C.
Papapetropoulos, D.A.
Περιοδικό:
JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS
Εκδότης:
American Society for Pharmacology and Experimental Therapy
Λέξεις-κλειδιά:
calcium ion; cyclophilin D; hydrogen peroxide; hydrogen sulfide; hydrogen sulfide donor; morpholin 4 ium 4 methoxyphenyl(morpholino)phosphinodithioate; nitric oxide; nitric oxide synthase; sodium sulfide; thiovaline; unclassified drug; [10 oxo 10 [4 (3 thioxo 3h 1,2 dithiol5yl)phenoxy]decyl]triphenylphosphonium bromide; cardiotonic agent; hydrogen sulfide, animal cell; animal experiment; animal model; animal tissue; Article; cardiac muscle cell; controlled study; cytotoxicity; embryo; enzyme inhibition; enzyme phosphorylation; heart infarction size; heart muscle ischemia; heart protection; in vitro study; in vivo study; left anterior descending coronary artery; male; mitochondrial permeability; mouse; nonhuman; priority journal; rat; reperfusion injury; animal; cell line; drug effects; heart mitochondrion; human; metabolism; Myocardial Reperfusion Injury; pathology, Animals; Cardiotonic Agents; Cell Line; Humans; Hydrogen Sulfide; Male; Mice; Mitochondria, Heart; Myocardial Reperfusion Injury; Myocytes, Cardiac; Nitric Oxide
DOI:
10.1124/jpet.116.235119
