Review Athero- and thrombogenic actions of lysophosphatidic acid and sphingosine-1-phosphate Wolfgang Siess * Institute for Prevention of Cardiovascular Diseases, Medical Faculty, University of Munich, Pettenkoferstr. 9, D-80336, Munich, Germany Received 30 January 2002; accepted 30 January 2002 Abstract Lysophosphatidic acid (LPA) and sphingosine-1-phosphate (S1P) are potent bioactive phospholipids with specific and multiple effects on blood cells and cells of the vessel wall. Released by activated platelets, LPA and S1P mediate physiological wound healing processes such as vascular repair. Evidence is accumulating that these lipid mediators can, however, under certain conditions become athero- and thrombogenic molecules that might aggravate cardiovascular disease. For example, LPA present in minimally modified LDL and within the intima of atherosclerotic lesions may play a role in the early phase of atherosclerosis by inducing barrier dysfunction and increased monocyte adhesion of the endothelium, as well as in the late phase by triggering platelet activation and intra-arterial thrombus formation upon rupture of the atherosclerotic plaque. Moreover, LPA and S1P, by stimulating the proliferation of fibroblasts and by enhancing the survival of inflammatory cells are likely to play a central role in the excessive fibroproliferative and inflammatory response to vascular injury that characterizes the progression of atherosclerosis. Furthermore, LPA can cause the phenotypic dedifferentiation of medial vascular smooth muscle cells, and S1P is able to stimulate the migration and proliferation of intimal vascular smooth muscle cells; both processes ultimately lead to the formation of the neointima. Most importantly, as LPA and S1P bind to and activate multiple G-protein receptors, it emerges that the beneficial or harmful action of LPA and S1P are critically dependent on the expression profile of their receptor subtypes and their coupling to different signal transduction pathways in the target cells. By targeting specific subtypes of LPA and S1P receptors in selective cells of the vascular wall and blood, new strategies for the prevention and therapy of cardiovascular diseases can be envisioned. D 2002 Elsevier Science B.V. All rights reserved. Keywords: Lysophosphatidic acid; Sphingosine-1-phosphate; Atherosclerosis; Thrombosis; Vascular tone; Plaque stability; Endothelial dysfunction; Neo- intima; Platelet activation 1. Introduction Lysophosphatidic acid (LPA) and sphingosine-1-phos- phate (S1P) are potent bioactive lipids with specific and multiple effects on cells of the vessel wall and blood platelets [1,2]. They bind to distinct G-protein coupled receptors on the plasma membrane, previously termed Edg for endothelial differentiation gene [3]. S1P binds to five S1P receptors of the homology group 1 of Edg proteins, whereas LPA binds to three LPA receptors of the homology group 2 of Edg proteins (Table 1) [4–6]. The receptors either couple to one G-protein such as the S1P 1 receptor which activates only G i in various cell types, or to multiple G-proteins as it is the case for most of the LPA and S1P receptors (Table 1) [7,8]. Since the activation of the various G-proteins stimulates multiple signal transduction pathways, LPA and S1P can induce in the same cell many responses ranging from localized alterations of actin dynamics pro- ducing shape change and migration of the cell, to the stimulation of gene expression leading to enhanced cell proliferation and inhibition of apoptosis. The activation of the heterotrimeric protein G 12/13 induces mainly the Rho/ Rho kinase-mediated formation of actin stress fibers, focal 1388-1981/02/$ - see front matter D 2002 Elsevier Science B.V. All rights reserved. PII:S1388-1981(02)00173-7 Abbreviations: IL-2, interleukin-2; LPA, lysophosphatidic acid; LPC, lysophosphatidylcholine; MLC, myosin light chain; MCP-1, monocyte chemoattractant protein-1; mox-LDL, mildly oxidized LDL; e-NOS, endothelial NO-synthase; NO, nitric oxide; NPTyrPA, N-palmitoyl tyrosine phosphoric acid; NPSerPA, N-palmitoyl serine phosphoric acid; NF-nB, nuclear factor-nB; PA, phosphatidic acid; PLA 2 , phospholipase A 2 ; sPLA 2 - IIA, secretory class II phospholipase A 2 ; PLD, phospholipase D; S1P, sphingosine-1-phosphate; VSMCs, vascular smooth muscle cells * Tel.: +49-89-5160-4380; fax: +49-89-5160-4382. E-mail address: wolfgang.siess@klp.med.uni-muenchen.de (W. Siess). www.bba-direct.com Biochimica et Biophysica Acta 1582 (2002) 204 – 215