TT_I_P: Theoretical and Translational Medicine I. Posters
Dina Wafa, Krisztina Paulik, Petra Szilágyi, Zoltán Benyó, Zsuzsanna Miklós
Institute of Translational Medicine, Semmelweis University, 1094 Budapest, Hungary
Introduction: Sphingosine-1-phosphate (S1P) is a lipid mediator and its cardiovascular effects are mediated mostly via S1P1-3 receptors. In our previous study we observed a massive coronary flow (CF) reducing effect of S1P (45%) that resulted in the drop of contractile function. This effect was moderated in S1P3-KO, but not in S1P2-KO animals.
Aims: In our recent study we aimed to better characterize the signaling mechanisms behind the effects of S1P.
Method: Experiments were conducted on isolated Langendorff-perfused murine hearts. Left ventricular pressure and CF were continuously monitored. S1P (10-6 M) or its vehicle was infused to the perfusion line for 5 minutes followed by a 20-min wash-out period. Experiments were carried out in WT, sm-Gq/11-KO, sm-G12/13-KO, eNOS-KO and PTX pretreated mice.
Results: Inhibition of the S1P1 receptor by its selective inhibitor W146 did not influence the S1P-induced CF reduction and decline in contractile function. Whereas both in the presence of the selective S1P2 inhibitor JTE-013 and the selective S1P3 inhibitor TY52156, the reduction of coronary perfusion and decline in heart function were diminished. Simultaneous inhibition of S1P2 and S1P3 abolished the effect of S1P on CF (10%). Deletion of endothelial NO-synthase, inhibition of endothelin A receptor by BQ123, smooth muscle specific deletion of Gq/11 or G12/13 did not influence, whereas PTX pretreatment enhanced the CF reducing effect of S1P (70%).
Conclusion: We observed a massive CF reducing effect of S1P mediated via S1P2 and S1P3, presumably via redundant pathways. Interestingly, the Gi/o protein seems to play a role in the response. This process might have relevance in acute coronary events when a large amount of S1P is released due to platelet activation.
Funding: The research was funded by the Hungarian National Research, Development and Innovation Office (K-112964, K-125174 and NVKP_16-1-2016-0042) as well as by the Higher Education Institutional Excellence Program of the Ministry of Human Capacities in Hungary, within the framework of the Molecular Biology thematic program of the Semmelweis University and supported by the EFOP-3.6.3-VEKOP-16-2017-00009 grant and by Dr. Korányi András Foundation.
Semmelweis University, Doctoral School of Theoretical and Translational Medicine