Pharmacological postconditioning against myocardial infarction with a slow-releasing hydrogen sulfide donor, GYY4137
This is the author accepted manuscript. The final version is available from Elsevier via the DOI in this record.
Reason for embargo
Exogenous hydrogen sulfide (H2S) protects against myocardial ischemia/reperfusion injury but the mechanism of action is unclear. The present study investigated the effect of GYY4137, a slow-releasing H2S donor, on myocardial infarction given specifically at reperfusion and the signalling pathway involved. Thiobutabarbital-anesthetised rats were subjected to 30 minutes of left coronary artery occlusion and 2 hours reperfusion. Infarct size was assessed by tetrazolium staining. In the first study, animals randomly received either no treatment or GYY4137 (26.6, 133 or 266 μmol kg−1) by intravenous injection 10 minutes before reperfusion. In a second series, involvement of PI3 K and NO signalling were interrogated by concomitant administration of LY294002 or L-NAME respectively and the effects on the phosphorylation of Akt, eNOS, GSK-3β and ERK1/2 during early reperfusion were assessed by immunoblotting. GYY4137 266 μmol kg−1 significantly limited infarct size by 47% compared to control hearts (P < 0.01). In GYY4137-treated hearts, phosphorylation of Akt, eNOS and GSK-3β was increased 2.8, 2.2 and 2.2 fold respectively at early reperfusion. Co-administration of L-NAME and GYY4137 attenuated the cardioprotection afforded by GYY4137, associated with attenuated phosphorylation of eNOS. LY294002 totally abrogated the infarct-limiting effect of GYY4137 and inhibited Akt, eNOS and GSK-3β phosphorylation. These data are the first to demonstrate that GYY4137 protects the heart against lethal reperfusion injury through activation of PI3 K/Akt signalling, with partial dependency on NO signalling and inhibition of GSK-3β during early reperfusion. H2S-based therapeutic approaches may have value as adjuncts to reperfusion in the treatment of acute myocardial infarction.
QK acknowledges the generous support of the Iraqi Ministry of Higher Education and Scientific Research. RT is the recipient of The Brian Ridge Scholarship.
Available online 1 July 2016