RT Journal Article
SR Electronic
T1 Cardioprotection by H2S donors: nitric oxide-dependent and -independent mechanisms
JF Journal of Pharmacology and Experimental Therapeutics
JO J Pharmacol Exp Ther
FD American Society for Pharmacology and Experimental Therapeutics
SP jpet.116.235119
DO 10.1124/jpet.116.235119
A1 Athanasia Chatzianastasiou
A1 Sofia-Iris Bibli
A1 Ioanna Andreadou
A1 Panagiotis Efentakis
A1 Nina Kaludercic
A1 Mark E Wood
A1 Matthew Whiteman
A1 Fabio Di Lisa
A1 Andreas Daiber
A1 Vangelis G Manolopoulos
A1 Csaba Szabo
A1 Andreas Papapetropoulos
YR 2016
UL http://jpet.aspetjournals.org/content/early/2016/06/24/jpet.116.235119.abstract
AB 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 aim of the present study was to compare the cardioprotective actions of representative H2S donors from different classes and to study their mechanisms of action in myocardial injury in vitro and in vivo. Exposure of cardiomyocytes to H2O2 lead to significant cytotoxicity which was inhibited by sodium sulfide (Na2S), thiovaline (TV), GYY4137 and AP39. 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 NOS in vivo blocked only the beneficial effect of Na2S. Moreover, Na2S, but not AP39, administration enhanced endothelial NOS and vasodilator stimulated phosphoprotein phosphorylation. 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 mitochondrial Ca2+ retention capacity, an evidence of decreased propensity to undergo permeability transition. We conclude that although all H2S donors tested limit infarct size, the pathways involved were not conserved. Na2S had no direct effects on PTP opening and its action was NO-dependent. In contrast, the cardioprotection exhibited by AP39, could result from a direct inhibitory effect on PTP, acting at a site different than CypD.