Lysophosphatidic acid in atherosclerotic diseases

Abstract

Lysophosphatidic acid (LPA) is a potent bioactive phospholipid. As many other biological active lipids, LPA is an autacoid: it is formed locally on demand, and it acts locally near its site of synthesis. LPA has a plethora of biological activities on blood cells (platelets, monocytes) and cells of the vessel wall (endothelial cells, smooth muscle cells, macrophages) that are all key players in atherosclerotic and atherothrombotic processes. The specific cellular actions of LPA are determined by its multifaceted molecular structures, the expression of multiple G-protein coupled LPA receptors at the cell surface and their diverse coupling to intracellular signalling pathways. Numerous studies have now shown that LPA has thrombogenic and atherogenic actions. Here, we aim to provide a comprehensive, yet concise, thoughtful and critical review of this exciting research area and to pinpoint potential pharmacological targets for inhibiting thrombogenic and atherogenic activities of LPA. We hope that the review will serve to accelerate knowledge of basic and clinical science, and to foster drug development in the field of LPA and atherosclerotic/atherothrombotic diseases.

Figure 1

LPA-induced platelet signalling during platelet shape change. Activation of the LPA₅ receptor coupled to the heterotrimeric G13 protein stimulates Rho and Rho-kinase. The subsequent bifurcating pathway directed to either the myosin-binding subunit of MLC phosphatase or the LIM-kinase 1 leads to enhanced phosphorylation of MLC and stimulation of phospho-cofilin turnover, respectively. Phosphorylated myosin develops actin-activated ATPase activity, interacts with F-actin, and assembles into filaments, whereas cofilin regulates actin dynamics by enhancing both actin-polymerization and actin filament severing. These cytoskeleton changes underlie the folding of the surface membrane, the formation of pseudopods and the contractile wave centralizing the secretory granules during platelet shape change.

Figure 2

Hypothetical role of plaque LPA and the platelet LPA₅ receptor in acute atherothrombosis after plaque rupture. LPA in the lipid core of atherosclerotic plaques may act as a cofactor with platelet-adhesive matrix proteins such as collagen type I and III in platelet activation (van Zanten et al., 1994; Penz et al., 2005; Schulz et al., 2008). These matrix proteins are over-expressed in plaques as compared with healthy arterial intima. LPA induces, through binding to the LPA₅ receptor, shape change of circulating platelets and has a synergistic effect with ADP at inducing platelet aggregation and thrombus formation. ADP is secreted from dense granules of platelets adhering to the collagenous matrix of the ruptured cap. GPVI, glycoprotein VI.

Figure 3

LPA promotes the accumulation of macrophages in atherosclerotic lesions. The moxLDL leads to increased formation of LPC, which is converted by endothelial-derived ATX into LPA. LPA triggers the release of the chemokine CXCL1 from endothelial cells through the activation of LPA₁ and LPA₃. CXCL1 is immobilized on the endothelial surface and induces the adhesion of monocytes to the vessel wall via its receptor CXCR2 on monocytes. These monocytes migrate into the subendothelial space and transform into macrophages, which are the primary cells in early atherosclerotic plaques.

Figure 4

LPA induces neointima formation after vascular injury. Following vascular injury, activated platelets adhere to the denuded surface of the vessel wall and medial SMCs undergo apoptosis. These early events after vascular injury may induce the production of LPA, which increases CXCL12 in the vessel wall through its receptors LPA₁ and LPA₃. CXCL12 is released into the circulation and recruits SPC via its receptor CXCR4 to the injury site. These SPCs differentiate into neointimal SMCs, which form the neointimal lesion.