A Novel Sphingosine-1-Phosphate Receptor 1 Antagonist Prevents the Proliferation and Relaxation of Vascular Endothelial Cells by Sphingosine-1-Phosphate

Abstract

Sphingosine-1-phosphate (Sph-1-P) is a bioactive plasma lipid which affects cell proliferation and migration, etc., through 5 receptors: sphingosine-1-phosphate receptors 1 (S1P 1 ) to 5 (S1P 5 ).1) Among these receptors, S1P 1 is the most studied and attractive pharmacological target because the S1P 1 agonism provokes lymphopeina 2) and immunosuppression in vivo. Meanwhile, S1P 1 antagonism is supposed to inhibit angiogenesis. 3,4) In the case of agonist compounds, the non-selective Sph-1-P receptor agonist FTY720 (fingolimod, Novartis International AG, Basel, Switzerland) is pre-registered as a drug of multiple sclerosis. Additionally, the S1P 1 specific agonist R-3477 (Actelion Pharmaceuticals Ltd., Basel, Switzerland) is being evaluated in Phase II and I studies as an immunosuppressant for autoimmune disease and organ transplantation, respectively. In the case of antagonist compounds, a preclinical report showed that the small interfering RNA for S1P 1 inhibited tumor growth 5) ; nevertheless, there have been no clinical reports on a chemical compound for the treatment of angiogenic diseases, such as diabetic retinopathy and solid tumors. This is presumably because there are few S1P 1 antagonists that are potent and selective in vivo.Both S1P 1 and S1P 3 also play a role in cardiovascular regulation. The intravenous (i.v.) administration of Sph-1-P at high doses of 100-200 mg/kg caused bradycardia in anesthetized rats.6,7) Moreover, the heart rate of S1P 3 homozygous knockout mice was unchanged by Sph-1-P administration. 7)These results indicate that Sph-1-P caused bradycardia via S1P 3 in the heart, at least in the case of mice. On the other hand, i.v. administration of Sph-1-P at a low dose of 10 mg/kg provoked transient hypotension without affecting the heart rate in anesthetized rats.6) In this case, it is expected that Sph-1-P caused vasodilation on the vascular endothelial cells via S1P 1 and S1P 3 , followed by activation of the endothelial isoform of nitric oxide synthase and NO production. [8][9][10][11] We previously reported that a S1P 1 antagonist, designated as chemical lead 2, showed anti-angiogenesis activity in a rabbit cornea model and inhibition of the swelling of mouse feet in an anti-type II collagen antibody-induced arthritis model. 12) Afterwards, we synthesized derivatives of chemical lead 2 to obtain more effective S1P 1 antagonists and determined the representatives, named as compounds 1 to 5. The aim of this study is to elucidate whether the derivatives inhibit the effect of Sph-1-P both in vitro and in vivo. Therefore, here we describe the Sph-1-P antagonistic activity of the representative derivatives, compounds 1 to 5, through several in vitro and in vivo assays focusing on the proliferation, migration, tube formation, and relaxation of vascular endothelial cells. A sphingosine-1-phosphate receptor 1 (S1P 1 ) antagonist is expected to be an anti-angiogenic compound; however, there are few reports that demonstrated that a S1P 1 inhibitor improved the disease state in an angiogeni...

Angiogenesis in the atherosclerotic plaque

“…S1P1 (or EDG-1), encoded by S1PR1 gene, is expressed in many cell types, particularly in cardiomyocytes and endothelial cells, where it plays a role in the development of the cardiovascular system [212] , [213] . S1P1 is coupled to a Gi protein that inhibits adenylate cyclase (AC) and stimulates MAPK and PLC/PI3K/Akt-induced signaling responses, such as eNOS activation, SMC relaxation, vasodilatation, permeability, migration, proliferation and tubulogenesis of endothelial cells [214] . S1P1 controls the trafficking of N-cadherin of endothelial cells and strengthens contacts between endothelial cells and pericytes [31] .…”

Pharmacological relevance and potential of sphingosine 1‐phosphate in the vascular system

“…Yonesu and co‐workers synthesized chemical compounds, which function as S1P 1 antagonists and show anti‐angiogenesis activity (Yonesu et al ., 2009). Synthesis of derivatives of these non‐S1P‐analogues yielded effective S1P 1 antagonists, which were named compounds 1 to 5 (Yonesu et al ., 2010). One derivate, compound 5, shows S1P 1 ‐mediated antagonistic effects on migration, proliferation and tube formation in HUVECs and moreover inhibits S1P‐induced hypertension in rats (Yonesu et al ., 2010).…”

Loss of neutral ceramidase increases inflammation in a mouse model of inflammatory bowel disease

“…On the other hand, S1P has been shown to serve quite the opposite functions. S1P binds to five different G-protein coupled receptors to induce proliferation and migration [10–13], as well as regulate inflammation, immune cell functions and trafficking [14, 15]. …”