Advertisement

Archive

Prostacyclin induction by high-density lipoprotein (HDL) in vascular smooth muscle cells depends on sphingosine 1- phosphate receptors: Effect of simvastatin

Journal: Thrombosis and Haemostasis
ISSN: 0340-6245
DOI: https://doi.org/10.1160/TH07-11-0675
Issue: 2008: 100/1 (July) pp. 1-171
Pages: 119-126

Prostacyclin induction by high-density lipoprotein (HDL) in vascular smooth muscle cells depends on sphingosine 1- phosphate receptors: Effect of simvastatin

María González-Díez, Cristina Rodríguez, Lina Badimon, José Martínez-González
Centro de Investigación Cardiovascular, CSIC-ICCC, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain

Keywords

gene expression, smooth muscle cells, atherothrombosis, Antiplatelet agents, lipoproteins

Summary

Prostacyclin (PGI2) is an important regulator of vascular homeostasis. Our goal was to analyze the role of sphingosine 1-phosphate (S1P) and its receptors in the up-regulation of cyclooxygenase- 2 (Cox-2) induced by HDL in human vascular smooth muscle cells (VSMC). S1P induces Cox-2 expression in a timeand dose-dependent manner at concentrations (0.02–1 μM) compatible with those present in physiological HDL levels.The effect was mimicked by dihydro-S1P (DhS1P), a S1P derivative that only acts through cell surface S1P receptors. Desensitization of S1P receptors with S1P (or DhS1P) abolished HDL-induced Cox-2 up-regulation and PGI2 release. Inhibition of S1P receptors by suramin (inhibitor of S1P3), JTE013 (inhibitor of S1P2) or VPC23019 (inhibitor of S1P1 and S1P3) reduced the up-regulation of Cox-2 induced by HDL and S1P. The combination of suramin and JTE013 increased the inhibitory effect compared to that observed in cells treated with each inhibitor alone. siRNA against S1P2 or S1P3 significantly reduced the ability of HDL and S1P to up-regulate Cox-2. Simvastatin induced over-expression of S1P3 and potentiated the induction of Cox-2 expression produced by HDL (or S1P). Finally, suramin, JTE013 and VPC23019 inhibited p38 MAPK and ERK1/2 signaling pathways activated by HDL (or S1P) and the downstream activation of CREB, a key transcription factor involved in Cox-2 transcriptional up-regulation.These results indicate that S1P receptors, in particular S1P2 and S1P3, are involved in the Cox-2-dependent effects of HDL on vascular cells. Strategies aimed to therapeutically modulate S1P or S1P receptors could be useful to improve cardiovascular protection.

You may also be interested in...

1.

Kenneth J. Clemetson, Jeannine M. Clemetson

Thromb Haemost 2008 99 3: 473-479

https://doi.org/10.1160/TH07-12-0718

2.

Andreas E. May, Tobias Geisler, Meinrad Gawaz

Thromb Haemost 2008 99 3: 487-493

https://doi.org/10.1160/TH07-11-0680

3.
Christian Schulz 1, Ildiko Konrad 1, Susanne Sauer 1, Lena Orschiedt 1, Maria Koellnberger 1, Reinhard Lorenz 2, Ulrich Walter 3, Steffen Massberg1,4

Thromb Haemost 2008 99 1: 190-195

https://doi.org/10.1160/TH07-03-0235