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(The FASEB Journal. 2002;16:1477-1487.)
© 2002 FASEB

Does the coronary risk factor low density lipoprotein alter growth and signaling in vascular smooth muscle cells?

IOANNA GOUNI-BERTHOLD and AGAPIOS SACHINIDIS*1

Medical Clinic II, University of Cologne, 50931 Cologne, Germany; and
* Center of Physiology and Pathophysiology, University of Cologne, 50931 Cologne, Germany

1Correspondence: Center of Physiology and Pathophysiology, University of Cologne, Robert-Koch Str. 39, 50931 Cologne, Germany. E-mail: A.Sachinidis{at}uni-koeln.de


   ABSTRACT
TOP
 ABSTRACT
BACKGROUND
 EFFECTS OF LDL ON...
 LDL SIGNAL TRANSDUCTION PATHWAYS
 SYNOPSIS AND CONCLUDING REMARKS
 PROSPECTS AND PREDICTIONS
 REFERENCES
 
There is increasing evidence that hypertension promotes low density lipoprotein (LDL) transportation into the subendothelial space of the vascular wall. Vascular smooth muscle cell (VSMC) proliferation plays an important role in the development and progression of cardiovascular diseases. Recently, several studies have demonstrated that LDL acts as a classic growth factor promoting VSMC growth via mitogenic signals normally elicited by classic growth factors. The present work summarizes current nontraditional concepts regarding possible cellular mechanisms through which hypertension and LDL may promote the development of atherosclerosis. Especially addressed are the possible effects of an elevated blood pressure in combination with LDL on VSMC growth. The new research concept concerning LDL as a growth factor and carrier for biological active phospholipids such as sphingosine-1-phosphate and sphingosylphosphorylcholine may contribute to an understanding of the pathogenesis of atherosclerosis by elevated high blood pressure—Gouni-Berthold, I., Sachinidis, A. Does the coronary risk factor low density lipoprotein alter growth and signaling in vascular smooth muscle cells?


Key Words: LDL • atherosclerosis • hypertension • signal transduction • MAP kinases • sphingosine-1-phosphate


   BACKGROUND
TOP
 ABSTRACT
 BACKGROUND
EFFECTS OF LDL ON...
 LDL SIGNAL TRANSDUCTION PATHWAYS
 SYNOPSIS AND CONCLUDING REMARKS
 PROSPECTS AND PREDICTIONS
 REFERENCES
 
VASCULAR SMOOTH MUSCLE cell (VSMC) proliferation plays an important role in the development and progression of cardiovascular diseases including hypertension and atherosclerosis (1 2 3) . Atherosclerosis and its complications (myocardial infarction, stroke, and peripheral vascular disease) are prevalent causes of morbidity and mortality in Western countries. According to the ‘response-to-injury’ model, hypertension and low density lipoproteins (LDL) are believed to be major independent risk factors for the development of atherosclerosis (4 , 5) . According to this traditional model, hypertension is one of several risk factors inducing endothelial damage and resulting in a deposition of LDL cholesterol (LDL-C) in atherosclerotic plaques. The earliest recognizable lesion of atherosclerosis is the fatty streak, an aggregation of lipid-rich macrophages and T lymphocytes within the innermost layer of the artery wall, the intima (3) . Several animal studies have shown that fatty streaks precede the development of intermediate lesions, which are composed of layers of macrophages and smooth muscle cells (3) . Intermediate lesions can develop into occlusive lesions called fibrous plaques. These are covered by a dense cap of connective tissue with embedded smooth muscle that usually overlays a core of lipid and necrotic debris. The fibrous plaque contains macrophages, smooth muscle cells, T lymphocytes, and connective tissue matrix proteins such as collagen and proteoglycans (3) . It is established that hypertension and elevated plasma LDL-C are independent risk factors for thicker carotid artery intima-media layers (6 7 8 9 10) . Increased intima-media thickness (IMT) of the common carotid arteries has been linked prospectively to the risk of coronary heart disease events (6 7 8) . Several epidemiological studies demonstrated that carotid IMT correlates well with cardiovascular risk factors (9 , 10) . More recently, the Los Angeles Epidemiological Study clearly demonstrated that elevated LDL-C was associated with increased IMT in hypertensive subjects (11) . Therefore, authors suggest that wall injury due to elevated blood pressure increases the susceptibility of the artery wall to LDL-C-mediated atherogenesis (11) . A close correlation between the concentration of LDL in human aortic intima and serum cholesterol level has been found (12) . It has been proposed that most of the circulating LDL is transported through the vascular endothelium by transcytosis (classic LDL receptor independent pathway) via plasmalemma vesicles that deliver LDL to other cells of the vascular wall (13) (Fig. 1 ). Elevated blood pressure increases transport of the circulating LDL into the subendothelial space (14 15 16) or prolongs the retention of LDL-C in the intima (Fig. 1) (17 , 18) . There is some evidence suggesting that LDL entrapped in the subendothelial space may be oxidized by the endothelial cells and thereby directly injure the endothelium via its toxic effects (19 , 20) . In general, the defining factor responsible for the formation of atheromatous plaques is an abnormal lipoprotein metabolism leading to hypercholesterolemia (21) and an abnormal proliferation of smooth muscle cells. LDL is considered to be the main atherogenic class of lipoproteins, and elevated levels of LDL represent one of the most important risk factors for atherosclerosis and cardiovascular morbidity (5) .



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  		Figure 1. Hypothesis and concept concerning LDL as a growth factor for vascular smooth muscle cells after its transcytosis from the lumen into the subendothelial space under the pathophysiological conditions of hypertension and hypercholesterolemia.

It has been established that VSMC in intimal lesions display increased expression of genes for growth factors, vascular cell adhesion molecule 1 (VCAM-1) and intracellular adhesion molecule 1 (ICAM-1) (3) . On the basis of these observations, Libby called them ‘activated’ VSMC (22) . Cell proliferation promoted by extracellular growth stimuli involves various intracellular signaling pathways leading to activation of gene transcription, DNA synthesis, and cell division. Protein phosphorylation, mediated by a complex regulatory network of protein kinases, plays a fundamental role in the signal transduction between cell surface and nucleus (23) . Even though there is a wide variety of mitogens and receptors, these signaling pathways often converge to the mitogen-activated protein kinases (MAPK), a group of serine/threonine protein kinases in mammalian cells (23 24 25) . In VSMC it has been shown that MAPK activation is important for PDGF- and oxLDL-induced cell proliferation (25 26 27 28) . The MAPK-mediated signal transduction pathways contribute to cell growth and differentiation (29) . Until now, four groups of MAPK have been characterized: the extracellular signal-regulated kinases (ERK)1/2, also termed p42/44 MAPK; the c-Jun N-terminal kinases (JNK)/stress-activated protein kinases(SAPK) 1/2/3; the p38 MAPK, also termed CSB (p38 {alpha}/ß/{gamma}/{delta}); and the ERK5 (also termed BMK1). They are all activated by specific MAPK kinases (MAPKK or MEK): MEK 1/2 for ERK1/2, MEK3/6 for the p38, MEK4/7 for the JNKs, and MEK5 for ERK5 (30) . The ERK1/2 kinases are rapidly stimulated in response to growth factors and are associated with cell proliferation and hypertrophy (31) . The p38 MAPK and the JNK/SAPK are strongly activated in response to stress stimuli such as ultraviolet radiation, heat shock, hyperosmolarity, and proinflammatory cytokines including TNF-{alpha} and IL-1 (32) . The MAPK are activated by phosphorylation on Tyr and Thr residues (33) by the dual specificity MAPK kinases, which are activated by Raf (31) . After their activation, MAPK are translocated to the nucleus, a step necessary to initiate entry to the S phase of the cell cycle (34 , 35) . After entering the nucleus, they induce activation and phosphorylation of regulatory proteins, including p90rsk, cPLA2, and transcription factors needed for the expression of genes involved in cell proliferation. In addition, activation of the cascade is required for passing through certain checkpoints in the cell cycle, such as G1/S and G2/M in proliferating cells in vitro (36) .

Assuming that hypertension promotes LDL transportation into the subendothelial space of the vascular wall, the present work summarizes current nontraditional concepts regarding possible cellular mechanisms through which hypertension and LDL may affect VSMC growth, thereby contributing to the development of cardiovascular diseases (Fig. 1) .


   EFFECTS OF LDL ON VSMC GROWTH
TOP
 ABSTRACT
 BACKGROUND
 EFFECTS OF LDL ON...
LDL SIGNAL TRANSDUCTION PATHWAYS
 SYNOPSIS AND CONCLUDING REMARKS
 PROSPECTS AND PREDICTIONS
 REFERENCES
 
The main pathophysiological function of LDL is to deliver cholesterol to VSMC and macrophages, which form foam cells (37) . LDL (native or oxidized) exerts mitogenic effects on VSMC (22 , 38 39 40 41 42 43) , endothelial cells (38 39 40 41 42 , 44) , and fibroblasts (38) . The response of the cells to LDL depends on LDL’s extracellular concentration and degree of oxidation. These responses include production of growth factors (45) , chemotaxis (46) , cell proliferation (47 , 48) , and induction of cytotoxicity (48) . In general, native and minimally oxidized LDL are defined by low content of lipid peroxidation derivatives (49) , whereas highly oxidized LDL is characterized by high levels of lipid peroxidation derivatives and severe apolipoprotein B alterations (50) . Whereas low concentrations of oxidized LDL (5–10 µg/ml) are mitogenic for VSMC, concentrations of 50–100 µg/ml tend to be cytotoxic (51) . In the literature, the terms ‘minimally oxidized’, ‘mildly oxidized’, ‘partly oxidized’ ‘minimally modified’, ‘moderately oxidized’, or simply ‘oxidized LDL’ are used quite arbitrarily. For simplicity and since the biological behavior of native and minimally oxidized LDL is quite similar, we will refer to native and minimally oxidized LDL as LDL and to the rest as oxidized LDL (oxLDL). LDL has been shown to act synergistically with other growth factors such as serotonin (released from activated platelets and a potent vasoactive substance) (52) , thromboxane A2 (49) , and PDGF-BB (39) to induce VSMC proliferation. In human plasma LDL conveys resistance to the antiproliferative effects of heparin on VSMC (53) .

LDL has an effect on the expression of various growth factors and growth factor receptors. For example, oxLDL elicits tyrosine phosphorylation of the EGF receptor in VSMC, most likely from derivatization through 4-hydroxy-2-nonenal (HNE) and activation of its signaling pathway (54) . The EGF receptor is a transmembrane receptor tyrosine kinase implicated in various biological processes such as cell proliferation and differentiation. Its activation is associated with stimulation of its intrinsic tyrosine kinase, autophosphorylation of its own tyrosine residues, and phosphorylation of intracellular substrate proteins (54) . Phosphotyrosines of the COOH-terminal domain of the EGF receptor may bind to SH2 domains of enzymatic or adaptor proteins, including phospholipase C-{gamma}1 43, GTPase-activating protein of p21ras (55) , syp phosphotyrosine phosphatase (56) , p85 subunit of phosphatidylinositol 3-kinase (PI3K) (57) , shc (58) , Grb-sos (59) , and Nck (60) .

LDL and oxLDL enhance production of PDGF-AA (61 62 63) and PDGF receptors in cultured human VSMCs (62) . Moreover, LDL increases the gene transcription of c-fos and egr-1, which are essential transcription factors for VSMC proliferation (3 , 64) . Locher et al. reported that LDL induces generation of thromboxane A2 (65) , a potent growth-promoting factor for VSMCs (66) . Up-regulation of the Ang II AT1 receptor by LDL has been observed in VSMCs resulting in an elevation of the functional AT1 receptors and a potentiation of the Ang II-induced DNA synthesis (41) . LDL is capable of up-regulating the thrombin receptor gene expression and enhancing the proliferative effects of thrombin on VSMCs (42) .

The proliferative effects of LDL could be mediated by the induction of an autocrine mitogenic circuit involving PDGF and FGF-ß (47) . Arterial VSMC express PDGF (67) ; the significance of this growth factor in atherosclerosis is supported by the restricted expression of PDGF receptors on the proliferating VSMC subset in the intima (68) , whereas expression is absent on stationary VSMC in the media (69) .

Finally, another mechanism through which LDL might induce VSMC proliferation is by stimulation of the monocyte chemotactic protein 1 (MCP-1) production (47 , 70) , since the rat homologue of human MCP-1 has been linked to VSMC proliferation and migration (71) .


   LDL SIGNAL TRANSDUCTION PATHWAYS
TOP
 ABSTRACT
 BACKGROUND
 EFFECTS OF LDL ON...
 LDL SIGNAL TRANSDUCTION PATHWAYS
SYNOPSIS AND CONCLUDING REMARKS
 PROSPECTS AND PREDICTIONS
 REFERENCES
 
Various signaling pathways are involved in the LDL and oxLDL effects on VSMC, including trimeric G-proteins and cAMP (72) , protein kinase C (PKC) (26 , 27 , 73) , and ceramide (74) . There is evidence that LDL as well as oxLDL stimulate the phosphoinositide (PI) catabolism (hydrolysis), which produces two second messengers: diacylglycerol (DAG) and inositol-1,4,5-triphosphate (IP3) (75 , 76) . DAG is known to activate PKC and IP3 to release Ca2+ from intracellular stores. Moreover, LDL elevates intracellular free calcium concentration (38) , stimulates the Na+/H+ exchange (77) , and promotes the expression of c-fos (75) and egr-1 (64) in VSMC. OxLDL activates phospholipase C (PLC), phospholipase A2 (PLA2), and phospholipase D (PLD) to generate DAG (78) . Another potential phospholipid that has been discussed as being responsible for the mitogenic effects of oxLDL is the platelet-activating factor (PAF), a vasoactive ether lipid acting through a G-protein-coupled receptor via stimulation of the PI turnover and triggering a broad array of biological actions (79) , including contraction (80) and growth (26) .

It has been shown that PKC down-regulation or inhibition as well as PI-PLC inhibition attenuates oxLDL-stimulated DNA synthesis and ERK1/2 stimulation in VSMC, indicating that some components of the MAPK signal involve PI-PLC- and PKC-mediated activation of intermediate kinases (81) . These are likely to be either Raf-1, which has been shown to be activated in a PKC-dependent manner (82) , or possibly MEK1/2, which is believed to be activated in a PKC-dependent manner (83) . Treatment with oxLDL increased the activity of membrane PKC but decreased that of cytosolic PKC, suggesting the translocation of PKC from cytosol to the membrane in the presence of oxLDL. The time course of the PKC activation by oxLDL has been shown to be essential for late responses such as proliferation and differentiation (84) .

LDL and oxLDL stimulate p44/p42 MAPK (85 , 86) and c-fos expression in aortic VSMCs. The involvement of a tyrosine kinase in the oxLDL-induced MAPK stimulation has been investigated, using the tyrosine kinase inhibitors genistein and herbimycin A, and revealed that the oxLDL-induced DNA synthesis is mediated through activation of tyrosine kinase whereas the oxLDL-induced MAPK activation is not (81) .

More recently, it has been shown that oxLDL strongly evoked phosphorylation and activation of p38 MAP kinase in rat VSMCs in concentration- and time-dependent manner, which was likely mediated via pertussis toxin (PTX) -sensitive G-proteins. The p38 MAP kinase activation was functionally associated with oxLDL-induced cytotoxicity in VSMC (87) .

Recently, it has been shown that LDL activates the p44/p42 MAPK as well as elevates Ca2+ via a PTX-sensitive pathway (38) . PD 98059, a MAP kinase kinase (MEK) inhibitor, remarkably attenuated the LDL-induced activation of MAP kinases and DNA synthesis (38) . SB203580, a specific p38 inhibitor, inhibits the oxLDL-induced DNA synthesis but only displays an inhibitory effect on p42/p44 MAPK activation at high concentrations, suggesting that an alternative pathway, such as the p38 MAPK, may be involved in the mitogenic effect of oxLDL in rat cultured VSMC. It has been shown that LDL stimulates not only the p42/p44 MAPK but also the p38 and the SAPK/JNK MAP in VSMC (88) . The LDL-induced early intracellular events in fibroblasts are mediated by a PTX-sensitive guanosine triphosphate (GTP) binding G-protein (Gi protein) -coupled receptor independent from its classic LDL receptor (LDL-R) (38) , and there is some evidence supporting the concept that in VSMC the mitogenic signaling pathway of LDL is not mediated by its classical receptor but through a putative Gi protein-coupled receptor. For example, an atypical LDL binding site on human VSMCs with a Kd of 50 µg/ml has been characterized that may mediate the LDL-induced PI catabolism and the elevation of Ca2+ in VSMC (89) . Since it has been reported that LDL stimulates PI catabolism and an increase in Ca2+ normally stimulated by receptors that are coupled to a PTX-insensitive Gq subfamily (90 , 91) , it may be assumed that atypical LDL-R is able to couple to Gi and Gq proteins. This phenomenon is described in the lysophosphatidic acid (LPA) receptor coupled to both PTX-sensitive (Gi) and -insensitive (Gq) protein (92 , 93) . A new G-protein-coupled receptor was found containing LDL binding domains that may be involved in the intracellular transduction pathway of LDL (94) . MAP kinase activation in response to G-protein coupled agonists has been reported for angiotensin II and vasopressin (95) . The mechanism by which the G-protein-coupled receptors activate the MAPK pathway is not completely understood. Yang et al. demonstrated recently that the mitogenic effects of oxLDL are mediated through a PTX-sensitive, G-protein-coupled receptor that involves activation of the Ras/Raf/MEK/MAPK pathway (96) . They showed that Ca2+ is required for these effects since removal of Ca2+ by the addition of BAPTA/AM plus EGTA significantly reduced oxLDL-induced [3H]thymidine incorporation and p42/44 MAPK activation (81) . It is well established that growth factors activate phosphorylation of protein kinases including tyrosine kinases, Ras, Raf-1, MEK and MAPK (24 , 97) . Ras, a small G-protein, regulates a variety of cellular processes including growth and differentiation of many cell types (98) . There much evidence suggesting that Ras is activated by various stimuli for growth and differentiation and that the activated Ras evokes the phosphorylation cascade of protein kinases including Raf-1, MEK1/2 and MAPK (24 , 97) . It has been shown that oxLDL- and PDGF-BB-induced p42/p44 MAPK activation is suppressed by transfection with the dominant negative mutant of Ras (H-Ras-15A) in VSMC (81) , as previously reported in other cell lines (99 , 100) . Several studies have shown that activated Ras binds and activates Raf-1, resulting in activation of MEK and MAPK (24 , 101 , 102) . In VSMC, the oxLDL- and PDGF-BB-induced MAPK activation are suppressed by transfection with a dominant negative mutant of Raf-1 (Raf-N4), suggesting that Raf-1 plays a key role in the oxLDL- and PDGF-BB-induced activation of MEK/MAPK cascade (81) .

The possibility that the effect of oxLDL on MAPK phosphorylation may be mediated via indirect autocrine mechanisms, including the release of VSMC-derived mitogenic neuroendocrine factors like endothelin 1 or angiotensin II, which are coupled to VSMC proliferation and activation of MAPK, is unlikely since these cellular responses have been reported not to be blocked by the endothelin 1 receptor antagonist BQ-123 or the angiotensin II receptor antagonist losartan (81) .

The mitogenic effects of oxLDL may be mediated via oxidation products. These include the lysophosphatidylcholine (LPC), which derives from the oxidation of phosphatidylcholine, reactive oxygen species (ROS) such as hydrogen peroxide (H2O2), superoxide anion, and the hydroxy radical, as well as the HNE, a major lipid peroxidation product (49) . It has been shown that formation of LPC in the oxLDL correlates well with its growth-stimulating effect (103) . Furthermore, LPC has been shown to mediate the synergistic effect of oxLDL with serotonin on vascular smooth muscle cell proliferation (104) , which may be responsible for VSMC migration and proliferation. Others have reported, however, that LPC itself is a mitogen for VSMC under serum-free conditions (105) . LPC and H2O2 induce ERK1/2 activation, c-fos and c-jun mRNA expression, and subsequent enhancement of activator protein 1 (AP-1) binding activity in VSMC (103 , 106 107 108) .

Sphingolipids have recently emerged as key signaling molecules involved in the regulation of cell growth and differentiation (109) . Activation of the sphingomyelin (SM) -ceramide pathway leads to SM hydrolysis and subsequent generation of ceramide, the backbone of all sphingolipids, which serves as an intracellular second messenger. Cytokines, nerve growth factor, anticancer drugs, and ionizing radiation have all been shown to activate the SM-ceramide pathway (109) . Cell-permeant ceramide or ceramide produced by treatment of intact cells with exogenous sphingomyelinase can mimic the effects of various SM-ceramide pathway activators. Various cellular responses such as cell proliferation (110) , differentiation (111) , or apoptosis (112) seem to be induced by SM hydrolysis and subsequent ceramide generation. The ceramide formed might be hydrolyzed by ceramidases to liberate the sphingoid base backbone (sphingosine), which can be reacetylated to ceramide or phosphorylated to sphingosine-1-phosphate (S1P) by sphingosine kinases (109) . Sphingosine kinase is activated by PDGF, phorbol esters, and other stimulatory factors (113) . It has been shown that the proliferation of VSMC induced by oxLDL is preceded by an increase in neutral sphingomyelinase activity and in sphingomyelin turnover to ceramide (114) and that the mitogenic effect of oxLDL in VSMC involves the combined activation of sphingomyelinase(s), ceramidase(s), and sphingosine kinase, resulting in the turnover of sphingomyelin to a number of sphingolipid metabolites, of which S1P at least has been shown to be critical for mitogenesis (114) . Whereas ceramide and sphingosine have recently been described as potent inhibitors of cell growth (109) , S1P has been found to be growth stimulatory for smooth muscle cells (115) . The mitogenic effects of S1P have been attributed to calcium mobilization, activation of PLD, and generation of the second messenger phosphatidic acid, engagement of the MAPK pathway, and activation of the transcription factor AP-1 (113) . One characteristic feature of these phospholipids is that their intracellular signaling pathway is mediated by PTX-sensitive Gi proteins (109 , 116 117 118) . It has been suggested that LPA and LPC are generated by phospholipase A2 hydrolysis during cellular oxidative modification of LDL (119) . OxLDL has been found to stimulate the SM-ceramide pathway through a protease-dependent mechanism and, as a consequence, activate p44/p42 MAPK and [3H]thymidine incorporation (114) .

Some investigators have identified the molecular structure of oxidized phospholipids in LDL that induce monocyte–endothelial interactions. These lipids were identified as 1-palmitoyl-2-(5-oxovaleryl)-sn-glycero-3-phosphocholine (m/z 594.3) and 1-palmitoyl-2-glutaryl-sn-glycero-3-phosphocholine (m/z 610.2) and may be important initiators of atherogenesis (120) . Our group has recently showed that at least part of the mitogenic effects of LDL are due to LDL-adherent factors such as S1P and sphingosylphosphorylcholine (SPC) (121) . We have documented that lipoprotein-adherent factors with sphingosine-1-phosphate S1P/SPC-like activity are responsible for the stimulation of the early intracellular signaling pathway observed by LDL and other lipoproteins (121) . We demonstrated that after delipidation of LDL with chloroform/methanol/water mixtures, a PTX-sensitive ‘signaling activity’ was found in one fraction. The term signaling activity was used to characterize fractions that cause an increase in intracellular free Ca2+ concentration or stimulate ERK1/2 and c-fos mRNA expression. After further analysis of this fraction by high-pressure liquid chromatography, a PTX-sensitive signaling activity was detected only in the fraction with a similar retention time as S1P and SPC, suggesting that LDL is a carrier for S1P and SPC. More recently, it has been proved that LDL contains great amounts of S1P (122 , 123) . The lysophospholipids S1P and SPC are related in their structure to LPA. Like the intracellular signaling pathway of LDL (38 , 121) , a characteristic of these bioactive lipids is that their intracellular signaling pathway is mediated by a PTX-sensitive Gi protein (92 , 93 , 109 , 124) .

Recently a cluster of lysophospholipid receptors has been discovered. It contains eight G-protein-coupled receptors with the colloquial name ‘Edg’ (an acronym for endothelial differentiation gene). There are eight Edg receptor genes in the human genome. Five of these encode S1P receptors (Edg-1, -3, -5, -6, and -8) (125 , 126) whereas the remaining three encode LPA receptors (Edg-2, -4, and -7) (127 , 128) . Edg-3 is also the receptor of SPC (129 , 130) . It has been suggested that the S1P-induced DNA synthesis and migration of VSMC is mediated through the Edg family of receptors (131) and that enhanced expression of Edg-1 in VSMC dramatically stimulates the proliferative and migratory responses to S1P (132 , 133) . Therefore, it can be proposed that Edg-related receptors may mediate the intracellular transduction pathway of LDL.

OxLDL stimulates the biosynthesis of lactosylceramide (LacCer), a glycosphingolipid present in endothelial and VSMC and which has been shown to stimulate the proliferation of VSMC (134) . OxLDL stimulates the synthesis of LacCer by activation of UDP-Gal:GlcCer, ß1–4 galtransferase (GalT-2). In turn, LacCer serves as a lipid second messenger that initiates a signal transduction pathway leading to cell proliferation. This signaling pathway includes LacCer-mediated activation of NADPH oxidase, which produces superoxide. Such superoxide molecules stimulate the GTP loading of p21ras. Subsequently, the kinase cascade (Raf-1, MEK2, and p44MAPK) is activated (135 , 136) . oxLDL, LacCer, or both stimulate the expression of proliferating cell nuclear antigen, also known as cyclin, and cell proliferation takes place (137) . D-threo-1-phenyl-2-decanoylamino-3-morpholino-1-propanol, an inhibitor of GalT-2, can abrogate the oxLDL-mediated activation of GalT-2, the signal kinase cascade noted above, as well as cell proliferation (138) .

A signaling pathway recently implicated in the proliferative effects of LDL on VSMC involves up-regulation of gp130, the signal-transducing element of the IL-6 receptor family, which renders the cells sensitive to trans-signaling through IL-6/soluble IL-6 receptor (sIL-6R) activation pathway (47) . It is known that IL-6/sIL-6R complexes form spontaneously in solution after their release from cells. The complexes can subsequently bind to, and activate cells that express the signal-transducing element gp130. This process, termed trans-signaling, is widely operative because gp130 is constitutively expressed in many cell types (139) . Quiescent VSMC express little gp130 but up-regulate the molecule when stimulated with IL-6/sIL-6R (140) . This drives the cell into a proliferative state. LDL has been found to be a second stimulus causing up-regulation of gp130, thus enhancing the efficiency of the trans-signaling circuit in VSMC (47) .

In general, LPA (141) , LPC (104) , and PAF (142) are present in oxLDL (their amount increasing in parallel to the degree of oxidation) while virtually absent in LDL. In a previous work we demonstrated that 1–5 µg/ml LPA induces an increase of DNA synthesis in VSMC whereas higher concentrations were toxic (124) . Therefore, it could be suggested that low levels of lipid peroxidation derivatives exert mitogenic effects on VSMC whereas higher concentrations are cytotoxic. S1P is another component of LDL, oxLDL, and HDL; key signaling molecules S1P and SPC (143) , the latter being a compound structurally closely related to S1P and present in LDL and oxLDL, have been implicated in cell growth by our group (121) and others (109 , 144) . It is interesting that oxidation of LDL markedly reduces the S1P content in association with a marked increase in cytotoxic LPC content (123) . Therefore, the conversion of the growth-promoting effects of LDL to cytotoxic effects can be attributed to the predominance of high levels of peroxidation derivatives LPC, PAF, and LPA at high degrees of LDL oxidation. On the other hand, S1P has been shown to induce expression of adhesion molecules such as VCAM-1 and E-selectin in endothelial cells (145) , suggesting atherogenic properties of S1P.

LDL is considered to be the main atherogenic class of lipoproteins; on the other hand, several epidemiological studies show an inverse correlation between the development of coronary artery disease and HDL (146 147 148) . The opposite actions of LDL (proatherogenic) and HDL (antiatherogenic) might initially appear contradictory in that both lipoproteins contain similar phospholipids, such as the S1P (121 , 149) . Several mechanisms have been proposed for the antiatherogenic functions of HDL. These include the promotion of the efflux of cholesterol from atherosclerotic plaques and inhibition of the oxidative modification of LDL by reverting the stimulatory effect of oxidized LDL on monocyte infiltration and by protecting endothelial cells from serum deprivation- and oxLDL-induced cytotoxicity (54 , 150) . HDL inhibits monocyte adhesion to endothelial cells, inhibits platelet activation (151) , and protects endothelial cells from apoptosis (149) . Furthermore, the HDL-associated enzyme paraoxonase inhibits the oxidation of LDL (152) . PAF-acetyl hydrolase, which circulates in association with HDL and is produced in the arterial wall by macrophages, degrades bioactive oxidized phospholipids (153) . Both enzymes actively protect hypercholesterolemic mice against atherosclerosis. Oxidized LDL inhibits these enzymes (152) . It has been shown that HDL prevents the oxidized LDL-induced inhibition of endothelial nitric oxide synthase (154) and has a direct inhibitory effect on the oxidized LDL-induced overexpression of ICAM-1 and VCAM-1 at the surface of endothelial cells (12 , 155) . Moreover, recent in vitro studies have suggested that HDL has endothelial cytoprotective actions (123) and is a carrier of endothelial survival factors such as SPC and lysosulfatide (149) . In contrast to HDL, LDL binds to arterial wall proteoglycans resulting in a prolonged and enhanced retention of LDL by the arterial wall (18) , a fact that has been associated with increased atherogenicity (17 , 156 , 157) . Thus, it is likely that under such pathophysiological conditions, an accumulation of LDL-adherent phospholipids in the intima and media of the vascular wall might occur. Furthermore, there is increasing evidence from in vitro studies that HDL prevents the uptake of oxLDL in human endothelial cells by reducing the number of caveolae available for LDL transcytosis (158) . However, in vivo HDL oxidation in the subendothelial space, where it can be found along with LDL, could favor the atherosclerotic process. The atherogenic properties of oxidized HDL result from some loss of their cholesterol effluxing capacity and from an inactivation of the lecithin-cholesterol acyltransferase, which is an HDL-associated enzyme involved in reverse cholesterol transport (153) . Finally, oxidized HDL could induce cholesterol accumulation in macrophages. Further in-depth investigation is needed to assess these antagonistic effects and their consequences for the atherosclerotic process.


   SYNOPSIS AND CONCLUDING REMARKS
TOP
 ABSTRACT
 BACKGROUND
 EFFECTS OF LDL ON...
 LDL SIGNAL TRANSDUCTION PATHWAYS
 SYNOPSIS AND CONCLUDING REMARKS
PROSPECTS AND PREDICTIONS
 REFERENCES
 
It is established that hypertension and elevated plasma LDL cholesterol are two major independent risk factors for the development of atherosclerosis (Fig. 1) . The prominent features of the atherosclerotic lesions include the proliferation of VSMCs, cholesteryl ester-loaded macrophage foam cells, extracellularly trapped LDL, and deposition of cholesterol. LDL cholesterol is transported into the cells by receptor-mediated endocytosis through binding to its classic LDL receptor via apo B100. However, in the last decade there is accumulating evidence that LDL contributes to the development of atherosclerosis not only by its function as a cholesterol transport particle but also by directly promoting the proliferation of several cell types acting via Gi protein-coupled receptors. Multiple signaling pathways, normally used by classic growth factors, have been implicated in the LDL-induced VSMC growth (Fig. 2 ). LDL and oxLDL promote expression of several classic growth factor receptors, thereby indirectly promoting cell proliferation (Fig. 2) . Furthermore, there is increasing evidence that LDL and oxLDL function as carrier for bioactive phospholipids like S1P, SPC, LPC, and LPA, thereby activating Gi protein-coupled receptors probably belonging to the Edg family.



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  		Figure 2. Intracellular transduction mechanisms of LDL/oxLDL and possible pathways through which they promote growth of cells participating in the pathogenesis of atherosclerosis.

However, there is a clear need for further research to develop Edg receptor antagonists in order to elucidate the significance of the described mechanisms in the pathophysiology of cardiovascular diseases.


   PROSPECTS AND PREDICTIONS
TOP
 ABSTRACT
 BACKGROUND
 EFFECTS OF LDL ON...
 LDL SIGNAL TRANSDUCTION PATHWAYS
 SYNOPSIS AND CONCLUDING REMARKS
 PROSPECTS AND PREDICTIONS
REFERENCES
 
Elevated levels of LDL cholesterol represent one of the most important risk factors for atherosclerosis and cardiovascular morbidity. First-line drugs for the treatment of hypercholesterolemia have been the 3-hydroxy-3-methylglutaryl-coenzyme A (HMGCoA) reductase inhibitors. Several clinical studies demonstrated that lowering of plasma cholesterol with HMGCoA reductase inhibitors reduces morbidity and mortality from coronary heart disease in diverse patient populations.

Abnormal VSMC proliferation and growth factors play an important role in the development and progression of cardiovascular diseases such as hypertension and atherosclerosis. A major target of cardiovascular research is to develop drugs acting as receptor antagonists of various growth factors, drugs that would therefore inhibit VSMC growth. Since there is increasing evidence that LDL cholesterol is a carrier of biological active phospholipids, we propose that antagonists of the Edg receptors alone or in combination with HMGCoA reductase inhibitors may be possible candidates for the treatment of cardiovascular diseases.


   ACKNOWLEDGMENTS
 
This work was supported by the Deutsche Forschungsgemeinschaft (Sa 568/4–1).


   REFERENCES
TOP
 ABSTRACT
 BACKGROUND
 EFFECTS OF LDL ON...
 LDL SIGNAL TRANSDUCTION PATHWAYS
 SYNOPSIS AND CONCLUDING REMARKS
 PROSPECTS AND PREDICTIONS
 REFERENCES
 

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