Pharmacological postconditioning against myocardial infarction with a slow-releasing hydrogen sulfide donor, GYY4137

Article English OPEN
Karwi, Qutuba ; Whiteman, Matthew ; Wood, Mark E. ; Torregrossa, Roberta ; Baxter, Gary (2016)

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 30min of left coronary artery occlusion and 2h reperfusion. Infarct size was assessed by tetrazolium staining. In the first study, animals randomly received either no treatment or GYY4137 (26.6, 133 or 266μmolkg-1) by intravenous injection 10min before reperfusion. In a second series, involvement of PI3K 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 266μmolkg-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 PI3K/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.
  • References (60)
    60 references, page 1 of 6

    ALEXANDER, B. E., COLES, S. J., FOX, B. C., KHAN, T. F., MALISZEWSKI, J., PERRY, A., PITAK, M. B., WHITEMAN, M. & WOOD, M. E. 2015. Investigating the generation of hydrogen sulfide from the phosphonamidodithioate slow-release donor GYY4137. Medicinal Chemical Communications, 6, 1649-1655.

    BARSUKEVICH, V., BASALAY, M., SANCHEZ, J., MROCHEK, A., WHITTLE, J., ACKLAND, G. L., GOURINE, A. V. & GOURINE, A. 2015. Distinct cardioprotective mechanisms of immediate, early and delayed ischaemic postconditioning. Basic Res Cardiol, 110, 452.

    BIAN, J. S., YONG, Q. C., PAN, T. T., FENG, Z. N., ALI, M. Y., ZHOU, S. & MOORE, P. K. 2006. Role of hydrogen sulfide in the cardioprotection caused by ischemic preconditioning in the rat heart and cardiac myocytes. J Pharmacol Exp Ther, 316, 670-8.

    BIBLI, S. I., ANDREADOU, I., CHATZIANASTASIOU, A., TZIMAS, C., SANOUDOU, D., KRANIAS, E., BROUCKAERT, P., COLETTA, C., SZABO, C., KREMASTINOS, D. T., ILIODROMITIS, E. K. & PAPAPETROPOULOS, A. 2015. Cardioprotection by H2S engages a cGMP-dependent protein kinase G/phospholamban pathway. Cardiovasc Res, 106, 432-42.

    BURLEY, D. S. & BAXTER, G. F. 2009. Pharmacological targets revealed by myocardial postconditioning. Curr Opin Pharmacol, 9, 177-88.

    BURLEY, D. S., FERDINANDY, P. & BAXTER, G. F. 2007. Cyclic GMP and protein kinase-G in myocardial ischaemia-reperfusion: opportunities and obstacles for survival signaling. Br J Pharmacol, 152, 855-69.

    CABRERA-FUENTES, H. A., ALBA-ALBA, C., ARAGONES, J., BERNHAGEN, J., BOISVERT, W. A., BOTKER, H. E., CESARMAN-MAUS, G., FLEMING, I., GARCIA-DORADO, D., LECOUR, S., LIEHN, E., MARBER, M. S., MARINA, N., MAYR, M., PEREZ-MENDEZ, O., MIURA, T., RUIZ-MEANA, M., SALINAS-ESTEFANON, E. M., ONG, S. B., SCHNITTLER, H. J., SANCHEZVEGA, J. T., SUMOZA-TOLEDO, A., VOGEL, C. W., YARULLINA, D., YELLON, D. M., PREISSNER, K. T. & HAUSENLOY, D. J. 2016. Meeting report from the 2nd International Symposium on New Frontiers in Cardiovascular Research. Protecting the cardiovascular system from ischemia: between bench and bedside. Basic Res Cardiol, 111, 7.

    CALVERT, J. W., JHA, S., GUNDEWAR, S., ELROD, J. W., RAMACHANDRAN, A., PATTILLO, C. B., KEVIL, C. G. & LEFER, D. J. 2009. Hydrogen sulfide mediates cardioprotection through Nrf2 signaling. Circ Res, 105, 365-74.

    CHUAH, S. C., MOORE, P. K. & ZHU, Y. Z. 2007. S-allylcysteine mediates cardioprotection in an acute myocardial infarction rat model via a hydrogen sulfide-mediated pathway. Am J Physiol Heart Circ Physiol, 293, H2693-701.

    DAS, A., SAMIDURAI, A., HOKE, N. N., KUKREJA, R. C. & SALLOUM, F. N. 2015. Hydrogen sulfide mediates the cardioprotective effects of gene therapy with PKG-Ialpha. Basic Res Cardiol, 110, 42.

  • Related Research Results (1)
  • Metrics
    0
    views in OpenAIRE
    0
    views in local repository
    24
    downloads in local repository

    The information is available from the following content providers:

    From Number Of Views Number Of Downloads
    Online Research @ Cardiff - IRUS-UK 0 24
Share - Bookmark