PhD Scientific Days 2022

Translational Medicine II. (Poster discussion will take place in the Aula during the Coffee Break)

Role of the Sphingosine-1-phosphate in the Regulation of Coronary Circulation

Text of the abstract

Introduction:
Sphingosine-1-phosphate (S1P) belongs to the group of lipid mediators. Its cardiovascular effects are mediated via S1P1-3 G-protein coupled receptors. In a previous study, we observed a significant decrease in coronary flow (CF) by S1P in isolated murine hearts. This effect was moderated in S1P3 KO mice.
Aims:
The aim of the present study was to delineate the role of S1P1 and S1P2 receptors and to identify the potential intracellular signaling pathways in the S1P coronary effect. We also wanted to clarify if endothelial vasoactive mediators participated in S1P CF effects.
Methods:
In our experiments, we used isolated, Langendorff perfused hearts of wild type (WT), pertussis toxin (PTX) pretreated WT, endothelial nitric-oxide synthase (eNOS KO) and smooth muscle specific S1P1 (sm-S1P1 KO) or Gαq/11 (sm-Gαq/11 KO) gene deficient mice. CF and left ventricular pressure changes were monitored continuously. We infused S1P (10-6 M) to the perfusate for 5 minutes in the presence of pharmacological inhibitors or their vehicles. We used JTE013 and TY52156 to inhibit S1P2 and S1P3, respectively. To block signaling pathways, BQ123 (endothelin A inhibitor) and Y27632 (Rho-associated protein kinase - ROCK - inhibitor) were applied.
Results:
Individual administration of S1P2 and S1P3 inhibitors reduced, whereas their coadministration abolished the CF reducing effect of S1P (maximum decrease in CF: WT: 62±5%; JTE013: 32±6%; TY52156: 28±6%; JTE013+TY52156: 15±6%; p<0.05 vs. WT; n=11,6,7,6). On the other hand, in sm-S1P1 KO hearts enhanced CF response to S1P was observed.
Y27632 moderated the S1P effect, whereas in sm-Gαq/11 KO hearts it was unchanged. However, CF decrease became more pronounced when we inhibited the Gαi/o protein with PTX (WT: 44±8%; PTX: 70±5%; p<0.05 vs. WT; n=5,8). BQ123 and deletion of eNOS had no effect on the CF response to S1P.
Conclusion:
S1P-dependent coronary constriction is mediated by S1P2 and S1P3 receptors via ROCK. Via S1P1 and Gαi/o-protein, S1P can also induce vasodilation, in which the cyclooxygenase-2 - prostacyclin pathway may play a role. Endothelial NO and endothelin-1 have no role in the CF regulatory effects of S1P. These processes may be of relevance in acute coronary syndrome, when there is a massive release of S1P.
Funding: K-135683, K-125174, Dr. Korányi András Foundation