Cardioprotection by H2S Donors: Nitric Oxide-Dependent and -Independent Mechanisms

Abstract

Hydrogen sulfide (H 2 S) is a signaling molecule with protective effects in the cardiovascular system. To harness the therapeutic potential of H 2 S, a number of donors have been developed. The present study compares the cardioprotective actions of representative H 2 S donors from different classes and studies their mechanisms of action in myocardial injury in vitro and in vivo. Exposure of cardiomyocytes to H 2 O 2 led to significant cytotoxicity, which was inhibited by sodium sulfide (Na 2 S), 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 Na 2 S and TV, but not GYY4137 and AP39, against H 2 O 2 -induced cardiomyocyte injury. Mice subjected to left anterior descending coronary ligation were protected from ischemia-reperfusion injury by the H 2 S donors tested. Inhibition of nitric oxide synthase (NOS) in vivo blocked only the beneficial effect of Na 2 S. Moreover, Na 2 S, but not AP39, administration enhanced the phosphorylation of endothelial NOS and vasodilator-associated phosphoprotein. Both Na 2 S 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 21 retention capacity, which is evidence of decreased propensity to undergo permeability transition. We conclude that although all the H 2 S donors we tested limited infarct size, the pathways involved were not conserved. Na 2 S 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.

The novel mitochondria-targeted hydrogen sulfide (H 2 S) donors AP123 and AP39 protect against hyperglycemic injury in microvascular endothelial cells in vitro

“…We found that AP39 and AP123 were effective against hyperglycemic injury at >1000-fold lower concentrations than Na 2 S in endothelial cells. The cytoprotective concentrations of the compounds (30–300 nM) are similar to the values previously reported for AP39 [34], [35], [56], [57]. The mitochondrial potential normalising and antioxidant effects of the compounds also confirm that H 2 S-mediated cytoprotection depends on its mitochondrial effect in hyperglycemic endothelial cells.…”

AP39, a mitochondria-targeting hydrogen sulfide (H2S) donor, protects against myocardial reperfusion injury independently of salvage kinase signalling

“…Viewed together, our data and those of Chatzianastasiou et al . () provide persuasive evidence that, unlike other H 2 S donors, AP39 mediates its cardioprotection by a mechanism that is independent of activation of the cytosolic components of the RISK signalling cascade.…”

“…Similarly, in the present study, we demonstrated that AP39 exerts an infarct‐sparing effect with an optimum cardioprotective dose of 1 μmol·kg −1 , fourfold higher than the effective dose in mouse reported by Chatzianastasiou et al . (). No haemodynamic data are available to compare AP39‐induced dose‐dependent improvement in post‐ischaemic functional recovery with Chatzianastasiou's paper.…”

“…Chatzianastasiou et al . () reported that AP39 did not phosphorylate either eNOS ser 1176 or VASP ser 239 after 10 min of reperfusion and its cardioprotection was not abolished by either L‐NAME or DT2, indicating a cGMP/PKG‐independent mechanism in the murine model. Their data are complementary to the fuller characterization of the potential cytosolic signalling targets of AP39 that we present here.…”

“…At the time of finalizing this manuscript, recent work with AP39 by Papapetropoulos's group (Chatzianastasiou et al ., ) has appeared. The main focus of Chatzianastasiou's work is ‘head‐to‐head’ comparison of infarct limitation by different H 2 S donors (Na 2 S, GYY4137, thiovaline and AP39) and elucidation of the role of NO in mediating protection.…”