Regulation of blood and vascular cell function by bioactive lysophospholipids

Abstract

Lysophosphatidic acid (LPA), its sphingolipid homolog sphingosine 1-phosphate (S1P) and several other related molecules constitute a family of bioactive lipid phosphoric acids that function as receptor-active mediators with roles in cell growth, differentiation, inflammation, immunomodulation, apoptosis and development. LPA and S1P are present in physiologically relevant concentrations in the circulation. In isolated cell culture systems or animal models, these lipids exert a range of effects that suggest that S1P and LPA could play important roles in maintaining normal vascular homeostasis and in vascular injury responses. LPA and S1P act on a series of G protein-coupled receptors, and LPA may also be an endogenous regulator of PPARgamma activity. In this review, we discuss potential roles for lysolipid signaling in the vasculature and mechanisms by which these bioactive lipids could contribute to cardiovascular disease.

Figure 1. Synthesis and inactivation of S1P and LPA

S1P is synthesized intracellularly by sphingosine kinase –catalyzed phosphorylation of sphingosine. Note that dihydrophingosine is also a substrate for this enzyme which forms dihydro S1P. These dihydro derivatives lack the double bond between the C4 and C5 carbon atoms. S1P can be converted to sphingosine by dephosphorylation catalyzed by a selective S1P phosphatase or the broader specificity lipid phosphate phosphatases. S1P can also be degraded by S1P lyase to form hexadecenal and ethanolamine phosphate. The predominant pathway for the production of extracellular LPA is from lysophospholipids, most likely lysophosphatidylcholine by the lysophospholipase D activity of autotaxin. LPA is inactivated by dephosphorylation catalyzed by the broad specificity lipid phosphate phosphatases to form monoacylglycerol. LPA can also be made by phospholipase A2 catalysed hydrolysis of phosphatidic acid. Intracellularly, LPA can be made de novo by acylation of glycerol 3-phosphate for synthesis of di- and tri-glycerides and phospholipids.

Figure 2. S1P and LPA homeostasis in the blood

S1P can be produced by platelets, vascular endothelium and erythrocytes. Adoptive transfer and transfusion experiments establish a critical role for erythrocytes in this process in mice. Erythrocytes sphingosine kinase and de novo synthesis of S1P may involve uptake of sphingosine (sph) from an undefined source, possibly vascular endothelium. S1P is carried in the blood bound to lipoproteins and serum albumin. LPA is formed by lysophospholipase D activity of autotaxin (ATX) which hydrolyzes circulating lyosphospholipids, predominantly LPC which may be formed as a by-product of cholesterol esterification or potentially generated by phospholipases acting on lipids in platelets, erythrocytes or membrane microparticles released from these cells. Like S1P, LPA and LPC are bound to serum albumin and lipoproteins