Sphingosine 1-Phosphate May Be a Major Component of Plasma Lipoproteins Responsible for the Cytoprotective Actions in Human Umbilical Vein Endothelial Cells

Abstract

Sphingosine 1-phosphate (S1P), a novel lipid mediator, is concentrated in the fraction of lipoproteins that include high density lipoprotein (HDL) and low density lipoprotein (LDL) in human plasma. Here, we show that oxidation of LDL resulted in a marked reduction in the S1P level in association with a marked accumulation of lysophosphatidylcholine (LPC). We therefore investigated the role of the lipoprotein-associated lipids especially S1P in the lipoprotein-induced cytoprotective or cytotoxic actions in human umbilical vein endothelial cells. The viability of the cells gradually decreased in the absence of serum or growth factors in the culture medium. The addition of oxidized LDL (ox-LDL) accelerated the decrease in the cell viability. LPC and 7-ketocholesterol mimicked ox-LDL actions. On the other hand, HDL and LDL almost completely reversed the serum deprivation-or ox-LDL-induced cytotoxicity. Exogenous S1P mimicked cytoprotective actions. Moreover, the S1P-rich fraction and chromatographically purified S1P from HDL exerted cytoprotective actions, but the rest of the fractions did not. The cytoprotective actions of HDL and S1P were associated with extracellular signal-regulated kinase (ERK) activation and were almost completely inhibited by pertussis toxin and PD98059, an ERK kinase inhibitor. The HDL-induced action was specifically desensitized in the S1P-pretreated cells. Taken together, these results indicate that the lipoprotein-associated S1P and the lipid receptor-mediated signal pathways may be responsible for the lipoprotein-induced cytoprotective actions. Furthermore, the decrease in the S1P content, in addition to the accumulation of cytotoxic substances such as LPC, may be important for the acquisition of the cytotoxic property to ox-LDL.

Involvement of Cdc42 Signaling in ApoA-I-induced Cholesterol Efflux

“…phosphatidylinositol-specific phospholipase C and phosphatidylcholine-specific phospholipase D) (15,16), and mobilization of intracellular Ca 2ϩ (16). However, work from our laboratory and other laboratories has demonstrated that these signaling events are generally not related to cholesterol efflux but rather account for other potentially anti-atherogenic effects of HDL, such as stimulation of cell proliferation or inhibition of apoptosis (12)(13)(14)16). Moreover, induction of these signaling pathways is not linked to apoA-I but rather to active lipids carried by HDL (10 -14, 16).…”

Dysfunctional high-density lipoproteins in coronary heart disease: implications for diagnostics and therapy

“…103 Although present on only one of 10 to 20 HDL particles, S1P contributes to several of the protective functions of HDL. For example, HDL-associated S1P appears to be important for the vasoprotective effects on endothelial cell survival, 104 109 and nitric oxide-dependent vasorelaxation. 20 It also inhibits vascular smooth muscle cell migration and chemokine production, 31, 110 cardiomyocyte apoptosis during hypoxia-reoxygenation, 111,112 and myocardial damage after ischemia/reperfusion.…”

Sphingosine-1-phosphate and modulation of vascular tone

“…It is important to note that the degree of eNOS activation by S1P is comparable to those attained by other classical eNOS agonists, including bradykinin or vascular endothelial growth factor (VEGF), suggesting quantitative importance of eNOS activation by S1P. 23,27 S1P has since been found to activate eNOS in many other cultured EC types, including human umbilical vein endothelial cells 28 (HUVEC) as well as bovine lung microvascular ECs. 25 In blood vessels isolated from rodent mesenteric arterioles and thoracic aorta, S1P activates eNOS via pertussis toxinsensitive G-protein-coupled receptor (GPCR) pathways.…”