Oxidized phospholipids in control of inflammation and endothelial barrier
2009; Elsevier BV; Volume: 153; Issue: 4 Linguagem: Inglês
10.1016/j.trsl.2008.12.005
ISSN1931-5244
AutoresPanfeng Fu, Konstantin G. Birukov,
Tópico(s)Heme Oxygenase-1 and Carbon Monoxide
ResumoThe levels of circulating oxidized phospholipids (OxPLs) become increased in chronic and acute pathologic conditions such as hyperlipidemia, atherosclerosis, increased intimamedia thickness in the patients with systemic Lupus erythematosus, vascular balloon injury, acute lung injury (ALI), and acute respiratory distress syndrome (ARDS). These pathologies are associated with inflammation and activation of endothelial cells. Depending on the biological context and the specific group of phospholipid oxidation products, OxPL may exhibit both proinflammatory and anti-inflammatory effects. This review will summarize the data showing a dual role of OxPL in modulation of chronic and acute inflammation as well as OxPL effects on pulmonary endothelial permeability. Recent reports show protective effects of OxPL in the models of endotoxin and ventilator-induced ALI and suggest a potential for using OxPL-derived cyclopenthenone-containing compounds with barrier-protective properties for drug design. These compounds may represent a new group of therapeutic agents for the treatment of lung syndromes associated with acute inflammation and lung vascular leak. The levels of circulating oxidized phospholipids (OxPLs) become increased in chronic and acute pathologic conditions such as hyperlipidemia, atherosclerosis, increased intimamedia thickness in the patients with systemic Lupus erythematosus, vascular balloon injury, acute lung injury (ALI), and acute respiratory distress syndrome (ARDS). These pathologies are associated with inflammation and activation of endothelial cells. Depending on the biological context and the specific group of phospholipid oxidation products, OxPL may exhibit both proinflammatory and anti-inflammatory effects. This review will summarize the data showing a dual role of OxPL in modulation of chronic and acute inflammation as well as OxPL effects on pulmonary endothelial permeability. Recent reports show protective effects of OxPL in the models of endotoxin and ventilator-induced ALI and suggest a potential for using OxPL-derived cyclopenthenone-containing compounds with barrier-protective properties for drug design. These compounds may represent a new group of therapeutic agents for the treatment of lung syndromes associated with acute inflammation and lung vascular leak. Increased levels of oxidized phospholipids (OxPL), which result from an enhanced generation of reactive oxygen species (ROS) or decreased antioxidant defense, are involved in certain pathologic conditions such as lung inflammation,1Yoshimi N. Ikura Y. Sugama Y. et al.Oxidized phosphatidylcholine in alveolar macrophages in idiopathic interstitial pneumonias.Lung. 2005; 183: 109-121Crossref PubMed Scopus (23) Google Scholar, 2Nakamura T. Henson P.M. Murphy R.C. Occurrence of oxidized metabolites of arachidonic acid esterified to phospholipids in murine lung tissue.Anal Biochem. 1998; 262: 23-32Crossref PubMed Scopus (35) Google Scholar ventilator-induced lung injury (VILI), atherosclerosis,3Subbanagounder G. Leitinger N. Schwenke D.C. et al.Determinants of bioactivity of oxidized phospholipids. Specific oxidized fatty acyl groups at the sn-2 position.Arterioscler Thromb Vasc Biol. 2000; 20: 2248-2254Crossref PubMed Scopus (200) Google Scholar, 4Watson A.D. Leitinger N. Navab M. et al.Structural identification by mass spectrometry of oxidized phospholipids in minimally oxidized low density lipoprotein that induce monocyte/endothelial interactions and evidence for their presence in vivo.J Biol Chem. 1997; 23: 13597-13607Crossref Scopus (696) Google Scholar and cell apoptosis.5Huber J. Vales A. Mitulovic G. et al.Oxidized membrane vesicles and blebs from apoptotic cells contain biologically active oxidized phospholipids that induce monocyte-endothelial interactions.Arterioscler Thromb Vasc Biol. 2002; 22: 101-107Crossref PubMed Scopus (256) Google Scholar, 6Chang M.K. Binder C.J. Miller Y.I. et al.Apoptotic cells with oxidation-specific epitopes are immunogenic and proinflammatory.J Exp Med. 2004; 200: 1359-1370Crossref PubMed Scopus (291) Google Scholar Cell membrane phospholipids and phospholipids contained in the circulating lipoproteins are the major source for OxPL. The cell membrane and low-density lipoproteins (LDLs) are enriched in phospholipids that contain polyunsaturated fatty acids, which are highly prone to oxidative modification. The formation of OxPL is initiated either by enzymes, such as lipoxygenase, or by reactive oxygen species (ROS). OxPL has been detected in human atherosclerotic lesions and the aortas of cholesterol-fed and heritable hyperlipidemic rabbits.3Subbanagounder G. Leitinger N. Schwenke D.C. et al.Determinants of bioactivity of oxidized phospholipids. Specific oxidized fatty acyl groups at the sn-2 position.Arterioscler Thromb Vasc Biol. 2000; 20: 2248-2254Crossref PubMed Scopus (200) Google Scholar, 4Watson A.D. Leitinger N. Navab M. et al.Structural identification by mass spectrometry of oxidized phospholipids in minimally oxidized low density lipoprotein that induce monocyte/endothelial interactions and evidence for their presence in vivo.J Biol Chem. 1997; 23: 13597-13607Crossref Scopus (696) Google Scholar, 7Hiltunen T.P. Gough P.J. Greaves D.R. Gordon S. Yla-Herttuala S. Rabbit atherosclerotic lesions express scavenger receptor AIII mRNA, a naturally occurring splice variant that encodes a non-functional, dominant negative form of the macrophage scavenger receptor.Atherosclerosis. 2001; 154: 415-419Abstract Full Text Full Text PDF PubMed Scopus (5) Google Scholar One major phospholipid present in plasma membrane and minimally modified LDL (MM-LDL) is 1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphorylcholine (PAPC), which generates a heterogeneous group of oxygenated full-length products or compounds during oxidation with truncated oxidized residues present at the sn-2 position. Biologically active "fragmented OxPL," in which the sn-2 fatty acid residues are oxidatively truncated, include 1-palmitoyl-2-(5-oxovaleroyl)-sn-glycero-phosphocholine (POVPC), 1-palmitoyl-2-glutaroyl-sn-glycero-phosphocholine (PGPC), and 5-keto-6-octendioic acid eater of 2-lyso-phosphocholine (KOdiA-PC). The other group of OxPLs, such as 1-palmitoyl-2-(5,6-epoxyisoprostane E2)-sn-glycero-3-phsphocholine (PEIPC) and 1-palmitoyl-2-(5,6-epoxycyclopentenone)-sn-glycero-3-phsphocholine (PECPC), represents "oxygenated OxPL," which is generated through the addition of oxygen atoms to the sn-2 fatty acid residues. The chemical structures of these biologically active OxPL are shown in Fig 1. In addition to phosphatidylcholine, other classes of OxPL that contain different polar heads and fatty acids, such as 1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphatidylethanolamine (PAPE) and 1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphatidylserine (PAPS), may undergo oxidative modification. This structural diversity accounts for a remarkable variety of biological activities of OxPL, which are described below. The ability of OxPL to induce monocyte adhesion or expression of interleukin-8 (IL-8) is demonstrated both for fragmented and oxygenated OxPL.8Lee H. Shi W. Tontonoz P. et al.Role for peroxisome proliferator-activated receptor alpha in oxidized phospholipid-induced synthesis of monocyte chemotactic protein-1 and interleukin-8 by endothelial cells.Circ Res. 2000; 87: 516-521Crossref PubMed Scopus (275) Google Scholar, 9Subbanagounder G. Wong J.W. Lee H. et al.Epoxyisoprostane and epoxycyclopentenone phospholipids regulate monocyte chemotactic protein-1 and interleukin-8 synthesis. Formation of these oxidized phospholipids in response to interleukin-1beta.J Biol Chem. 2002; 277: 7271-7281Crossref PubMed Scopus (171) Google Scholar In other biological systems, however, fragmented and oxygenated OxPLs exert different, or even opposite, effects. For example, sn-2-oxygenated, but not sn-2-fragmented phospholipids, exhibited barrier-protective properties in pulmonary endothelial cells (ECs). 10Birukov K.G. Bochkov V.N. Birukova A.A. et al.Epoxycyclopentenone-containing oxidized phospholipids restore endothelial barrier function via Cdc42 and Rac.Circ Res. 2004; 95: 892-901Crossref PubMed Scopus (141) Google Scholar Consistent with barrier-protective effects, sn-2-oxygenated, but not sn-2-fragmented, phospholipids activated Rac and Cdc42 small guanosine triphosphate (GTP)ase involved in signaling to the endothelial cells in the cytoskeleton. Furthermore, even molecules that contain a similar sn-2-fragmented residue exhibit different activities. POVPC and PGPC contain ω-aldehyde and ω-carboxyl groups, respectively. POVPC increases monocyte but not neutrophil binding to ECs.3Subbanagounder G. Leitinger N. Schwenke D.C. et al.Determinants of bioactivity of oxidized phospholipids. Specific oxidized fatty acyl groups at the sn-2 position.Arterioscler Thromb Vasc Biol. 2000; 20: 2248-2254Crossref PubMed Scopus (200) Google Scholar In addition, POVPC strongly inhibits the lipopolysaccharide-mediated induction of neutrophil binding and expression of E-selectin protein and messenger RNA (mRNA).3Subbanagounder G. Leitinger N. Schwenke D.C. et al.Determinants of bioactivity of oxidized phospholipids. Specific oxidized fatty acyl groups at the sn-2 position.Arterioscler Thromb Vasc Biol. 2000; 20: 2248-2254Crossref PubMed Scopus (200) Google Scholar In contrast, PGPC induces both monocyte and neutrophil binding as well as the expression of the E-selectin and the vascular cell adhesion molecule 1 (VCAM-1).11Leitinger N. Tyner T.R. Oslund L. et al.Structurally similar oxidized phospholipids differentially regulate endothelial binding of monocytes and neutrophils.Proc Natl Acad Sci U S A. 1999; 96: 12010-12015Crossref PubMed Scopus (229) Google Scholar Several lines of evidence reveal that both receptor-mediated and receptor-independent pathways are involved in OxPL-mediated cell activation. However, because of a broad spectrum of effects and diversity in chemical structures, it is reasonable to postulate that OxPL may interact with multiple receptors. Available data suggest several different families of receptors are activated by OxPL. It has previously been shown that OxPL may act by binding to a GPCR. Parhami et al12Parhami F. Fang Z.T. Yang B. Fogelman A.M. Berliner J.A. Stimulation of Gs and inhibition of Gi protein functions by minimally oxidized LDL.Arterioscler Thromb Vasc Biol. 1995; 15: 2019-2024Crossref PubMed Scopus (48) Google Scholar demonstrated that the treatment of aortic ECs with MM-LDL resulted in a saturable dose-dependent increase in cyclic adenosine monophosphate (cAMP) levels. The cAMP increase in response to MM-LDL treatment was caused by the stimulation of Gs complexes and inhibition of Gi complexes. Subsequent studies revealed involvement of different GPCR in the OxPL-mediated signaling pathway. During nonenzymatic deacylation and enzymatic hydrolysis, oxidized fatty acyl chains can be released from the sn-2 position of OxPL. Lipoprotein-associated phospholipase A2, which is also known as platelet-activation factor (PAF)-acetylhydrolase, catalyzes the conversion of OxPL into lysophospholipids, which can bind and activate various GPCRs. For example, lysophosphatidylcholine activates GPR4 and G2A receptors,13Kabarowski J.H. Zhu K. Le L.Q. Witte O.N. Xu Y. Lysophosphatidylcholine as a ligand for the immunoregulatory receptor G2A.Science. 2001; 293: 702-705Crossref PubMed Scopus (280) Google Scholar, 14Lum H. Qiao J. Walter R.J. et al.Inflammatory stress increases receptor for lysophosphatidylcholine in human microvascular endothelial cells.Am J Physiol. 2003; 285: H1786-H1789Google Scholar, 15Zhu K. Baudhuin L.M. Hong G. et al.Sphingosylphosphorylcholine and lysophosphatidylcholine are ligands for the G protein-coupled receptor GPR4.J Biol Chem. 2001; 276: 41325-41335Crossref PubMed Scopus (211) Google Scholar whereas lysophosphatidic acid stimulates LPA1–LPA4 receptors.16Tomura H. Mogi C. Sato K. Okajima F. Proton-sensing and lysolipid-sensitive G-protein-coupled receptors: a novel type of multi-functional receptors.Cell Signal. 2005; 17: 1466-1476Crossref PubMed Scopus (151) Google Scholar, 17Anliker B. Chun J. Cell surface receptors in lysophospholipid signaling.Semin Cell Dev Biol. 2004; 15: 457-465Crossref PubMed Scopus (180) Google Scholar Furthermore, some OxPLs have a similar structure to PAF and are considered as potential PAF receptor agonists. The major PAF-like lipid in oxidated LDL (OxLDL) is 1-O-hexadecyl-2-(butanoyl or butenoyl)-sn-glycero-3-phosphocholine.18Marathe G.K. Davies S.S. Harrison K.A. et al.Inflammatory platelet-activating factor-like phospholipids in oxidized low density lipoproteins are fragmented alkyl phosphatidylcholines.J Biol Chem. 1999; 274: 28395-28404Crossref PubMed Scopus (158) Google Scholar The activation of the PAF receptor by the OxPL resulted in IL-8 expression and monocyte binding to ECs.19Mao Y.J. Wang L. Wang W.J. Effect of ginkgolide B on the function of rat aorta smooth cells and U937 cells stimulated by oxLDL.Yao Xue Xue Bao. 2006; 41: 36-40PubMed Google Scholar, 20Beaudeux J.L. Said T. Ninio E. et al.Activation of PAF receptor by oxidised LDL in human monocytes stimulates chemokine releases but not urokinase-type plasminogen activator expression.Clin Chim Acta. 2004; 344: 163-171Crossref PubMed Scopus (11) Google Scholar However, some OxPL effects cannot be reproduced by the activation of the PAF receptor. As a well-recognized edemagenic agent, PAF does not mimic the barrier-protective effects of oxidized 1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphorylcholine (OxPAPC)21Birukova A.A. Chatchavalvanich S. Oskolkova O. Bochkov V.N. Birukov K.G. Signaling pathways involved in OxPAPC-induced pulmonary endothelial barrier protection.Microvasc Res. 2007; 73: 173-181Crossref PubMed Scopus (44) Google Scholar as well as induction of vascular endothelial growth factor (VEGF) by OxPAPC,22Oskolkova O.V. Afonyushkin T. Leitner A. et al.ATF4-dependent transcription is a key mechanism in VEGF up-regulation by oxidized phospholipids: critical role of oxidized sn-2 residues in activation of unfolded protein response.Blood. 2008; 112: 330-339Crossref PubMed Scopus (87) Google Scholar which suggests the involvement of receptor mechanisms rather than the PAF receptor. More recently, a Gs-coupled GPCR, prostaglandin E2 (PGE2) has been implicated in the activation of beta-1 integrin and the stimulation of monocyte binding to ECs induced by OxPAPC and PEIPC.23Li R. Mouillesseaux K.P. Montoya D. et al.Identification of prostaglandin E2 receptor subtype 2 as a receptor activated by OxPAPC.Circ Res. 2006; 98: 642-650Crossref PubMed Scopus (102) Google Scholar Butaprost, which is the specific agonist of PGE2, mimicked the effect of OxPAPC on the regulation of tumor necrosis factor-alpha (TNF- α) and IL-10 in monocyte-derived cells.23Li R. Mouillesseaux K.P. Montoya D. et al.Identification of prostaglandin E2 receptor subtype 2 as a receptor activated by OxPAPC.Circ Res. 2006; 98: 642-650Crossref PubMed Scopus (102) Google Scholar Furthermore, EP2 antagonist AH6809 blocked the activation of EP2 by OxPAPC in HEK293 cells and blocked the IL-10 response to PEIPC in monocytic THP-1 cells.23Li R. Mouillesseaux K.P. Montoya D. et al.Identification of prostaglandin E2 receptor subtype 2 as a receptor activated by OxPAPC.Circ Res. 2006; 98: 642-650Crossref PubMed Scopus (102) Google Scholar A line of evidence shows that PPAR γ, which is a nuclear receptor protein that plays an essential role in the regulation of genes, was activated by a fragmented alkyl phospholipid in OxLDL called hexadecyl azelaoyl phosphatidylcholine.24Davies S.S. Pontsler A.V. Marathe G.K. et al.Oxidized alkyl phospholipids are specific, high affinity peroxisome proliferator-activated receptor gamma ligands and agonists.J Biol Chem. 2001; 276: 16015-16023Crossref PubMed Scopus (238) Google Scholar In addition to PPARγ, PPARα may be also activated by OxPL or its components POVPC and PGPC. Furthermore, by using transient transfection assays, Delerive et al25Delerive P. Furman C. Teissier E. Fruchart J. Duriez P. Staels B. Oxidized phospholipids activate PPARalpha in a phospholipase A2-dependent manner.FEBS Lett. 2000; 471: 34-38Abstract Full Text Full Text PDF PubMed Scopus (173) Google Scholar demonstrated that OxLDL but not LDL activated PPARα dose dependently in ECs without affecting PPARα protein expression. Inhibitory analysis showed that phospholipase A2 but not lipoxygenases or cyclooxygenases was required for this activation.25Delerive P. Furman C. Teissier E. Fruchart J. Duriez P. Staels B. Oxidized phospholipids activate PPARalpha in a phospholipase A2-dependent manner.FEBS Lett. 2000; 471: 34-38Abstract Full Text Full Text PDF PubMed Scopus (173) Google Scholar CD36, which is an 88-kD transmembrane glycoprotein expressed on monocytes/macrophages, platelets, and microvascular endothelium, has been implicated as a putative receptor for OxLDL.26Podrez E.A. Poliakov E. Shen Z. et al.Identification of a novel family of oxidized phospholipids that serve as ligands for the macrophage scavenger receptor CD36.J Biol Chem. 2002; 277: 38503-38516Crossref PubMed Scopus (397) Google Scholar, 27Boullier A. Gillotte K.L. Horkko S. et al.The binding of oxidized low density lipoprotein to mouse CD36 is mediated in part by oxidized phospholipids that are associated with both the lipid and protein moieties of the lipoprotein.J Biol Chem. 2000; 275: 9163-9169Crossref PubMed Scopus (173) Google Scholar, 28Gillotte-Taylor K. Boullier A. Witztum J.L. Steinberg D. Quehenberger O. Scavenger receptor class B type I as a receptor for oxidized low density lipoprotein.J Lipid Res. 2001; 42: 1474-1482Abstract Full Text Full Text PDF PubMed Google Scholar More recently, the acyl chains of OxPL that protrude from the plasma membrane were defined as a key recognition site for macrophage binding to the cell surface. Two conserved, positively charged amino acids in CD36 (lysines at positions of 164 and 166) are critical for OxPL and OxLDL binding to CD36.29Kar N.S. Ashraf M.Z. Valiyaveettil M. Podrez E.A. Mapping and characterization of the binding site for specific oxidized phospholipids and oxidized low density lipoprotein of scavenger receptor CD36.J Biol Chem. 2008; 283: 8765-8771Crossref PubMed Scopus (85) Google Scholar In contrast to the implication of CD36 in OxLDL recognition by macrophage, work by Walton et al30Walton K.A. Hsieh X. Gharavi N. et al.Receptors involved in the oxidized 1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphorylcholine-mediated synthesis of interleukin-8. A role for Toll-like receptor 4 and a glycosylphosphatidylinositol-anchored protein.J Biol Chem. 2003; 278: 29661-29666Crossref PubMed Scopus (154) Google Scholar demonstrated that IL-8 induction by OxPAPC is independent of CD36 and mediated by toll-like receptor 4 (TLR4) and a 37-kDa glycosylphosphatidylinositol-anchored protein. In addition to receptor-mediated mechanisms, some effects of OxPL are probably not mediated by cell membrane receptors. For example, the sterol response element binding protein (SREBP) seems to be activated as a consequence of cholesterol depletion by OxPAPC in ECs through a nonreceptor mechanism.31Yeh M. Cole A.L. Choi J. et al.Role for sterol regulatory element-binding protein in activation of endothelial cells by phospholipid oxidation products.Circ Res. 2004; 95: 780-788Crossref PubMed Scopus (88) Google Scholar During oxidation, esterified fatty acids in phospholipids are converted into a series of highly electrophilic ketoaldehyde isomers, which are ready to adduct to proteins by direct chemical modification. A study by Brame et al32Brame C.J. Boutaud O. Davies S.S. et al.Modification of proteins by isoketal-containing oxidized phospholipids.J Biol Chem. 2004; 279: 13447-13451Crossref PubMed Scopus (75) Google Scholar provides a new insight into the mechanism by which OxPL influences the function of cardiac K+ channel, and it suggests a generalized cellular mechanism for the alteration of the membrane function as a consequence of oxidative stress induced by OxPL. By using N-biotin labeled OxPAPC, Gugiu et al33Gugiu B.G. Mouillesseaux K. Duong V. et al.Protein targets of oxidized phospholipids in endothelial cells.J Lipid Res. 2008; 49: 510-520Crossref PubMed Scopus (33) Google Scholar demonstrated the binding of OxPAPC to cytoskeleton-associated protein 4. This type II reversibly palmitoylated transmembrane protein regulates the tissue plasminogen activator on the surface of smooth muscle cells. The complexity of OxPL-induced effects on endothelial function is illustrated by a spectrum of cell response to OxPL, such as cytoskeletal remodeling, barrier function, inflammation, procoagulant activity, redox reaction, sterol metabolism, unfolded protein response (UPR), and angiogenesis. A microarray study showed that OxPAPC regulated the expression of over 700 genes in human aortic ECs.34Gargalovic P.S. Gharavi N.M. Clark M.J. et al.The unfolded protein response is an important regulator of inflammatory genes in endothelial cells.Arterioscler Thromb Vasc Biol. 2006; 26: 2490-2496Crossref PubMed Scopus (315) Google Scholar In this part, we will discuss mechanisms activated by OxPL and summarize the effects of OxPL on the vascular barrier. The accumulation of OxPL at the sites of chronic vascular inflammation such as atherosclerotic lesions and its role in propagation of this process is well recognized. The initial study by Henriksen et al35Henriksen T. Mahoney E.M. Steinberg D. Enhanced macrophage degradation of low density lipoprotein previously incubated with cultured endothelial cells: recognition by receptors for acetylated low density lipoproteins.Proc Natl Acad Sci U S A. 1981; 78: 6499-6503Crossref PubMed Scopus (864) Google Scholar formed the basis of the hypothesis that oxidation of LDL might be an important step in the atherogenesis process. Subsequent studies demonstrated the roles of OxPL in the activation of monocyte extravasation and adhesion, induction of inflammatory cytokines production, and increased thrombogenesis, as well as the effects on coagulation and redox balance. A characteristic feature of atherosclerosis is the accumulation of lipids in the lesion area. Numerous studies have clearly demonstrated that OxPL activates monocyte binding to the vascular EC; the initial event triggers vascular inflammation and atherosclerosis plaque formation and induces synthesis of monocyte-specific chemoattractants such as monocyte chemotactic protein 1 (MCP1) and monocyte/EC adhesion proteins.8Lee H. Shi W. Tontonoz P. et al.Role for peroxisome proliferator-activated receptor alpha in oxidized phospholipid-induced synthesis of monocyte chemotactic protein-1 and interleukin-8 by endothelial cells.Circ Res. 2000; 87: 516-521Crossref PubMed Scopus (275) Google Scholar Connecting segment 1 (CS1) fibronectin is an endothelial membrane protein that binds monocyte integrin α4β1, which causes the firm adhesion of monocyte with ECs.11Leitinger N. Tyner T.R. Oslund L. et al.Structurally similar oxidized phospholipids differentially regulate endothelial binding of monocytes and neutrophils.Proc Natl Acad Sci U S A. 1999; 96: 12010-12015Crossref PubMed Scopus (229) Google Scholar OxPAPC promotes the surface deposition of the CS-1 fibronectin, which is mediated by increased R-Ras activity and decreased H-Ras activity. In this model, OxPAPC increased cAMP levels, which are responsible for R-Ras activation. In turn, R-Ras activated PI3 K, which results in the activation of α5β1 integrin on the apical surface.36Cole A.L. Subbanagounder G. Mukhopadhyay S. Berliner J.A. Vora D.K. Oxidized phospholipid-induced endothelial cell/monocyte interaction is mediated by a cAMP-dependent R-Ras/PI3-kinase pathway.Arterioscler Thromb Vasc Biol. 2003; 23: 1384-1390Crossref PubMed Scopus (125) Google Scholar A candidate receptor that mediates this pathway is prostaglandin receptor EP2,23Li R. Mouillesseaux K.P. Montoya D. et al.Identification of prostaglandin E2 receptor subtype 2 as a receptor activated by OxPAPC.Circ Res. 2006; 98: 642-650Crossref PubMed Scopus (102) Google Scholar which belongs to the GPCR family. EP2 agonists increased the activation of beta 1 integrin. A line of evidence suggests lipoxygenase pathway as an alternative mechanism that regulates OxPL-induced monocyte adhesion. The treatment of ECs with a lipoxygenase inhibitor, but not cyclooxygenase, decreased MM-LDL and POVPC-induced monocyte binding to ECs.37Huber J. Furnkranz A. Bochkov V.N. et al.Specific monocyte adhesion to endothelial cells induced by oxidized phospholipids involves activation of cPLA2 and lipoxygenase.J Lipid Res. 2006; 47: 1054-1062Crossref PubMed Scopus (57) Google Scholar Furthermore, the addition of 12(S)- hydroperoxy tetraenoic eicosatetraenoic acid reversed the inhibitory effects of a lipoxygenase inhibitor on monocyte binding. Importantly, the mechanism of OxPL-induced monocyte binding to ECs is different from that induced by other inflammatory factors, such as lipopolysaccharide (LPS), TNFα, or IL-1. OxPL does not upregulate intercellular adhesion molecule-1 (ICAM-1), VCAM-1, and E-selectin expression, but it upregulates MCP1, CS1, and P-selectin, which leads to selective monocyte, but not neutrophil, adhesion to the vascular endothelium. Evidence indicates that OxPL increases the expression of several chemokines, including MCP-1, IL-8, IL-6, macrophage inflammatory protein-1 alpha (MIP-1 α), MIP-1 β, and growth-related protein α, which are described well in previous reviews.38Bochkov V.N. Inflammatory profile of oxidized phospholipids.Thromb Haemost. 2007; 97: 348-354Crossref PubMed Scopus (67) Google Scholar, 39Bochkov V.N. Leitinger N. Anti-inflammatory properties of lipid oxidation products.J Mol Med. 2003; 81: 613-626Crossref PubMed Scopus (76) Google Scholar, 40Birukov K.G. Oxidized lipids: the two faces of vascular inflammation.Curr Atheroscler Rep. 2006; 8: 223-231Crossref PubMed Scopus (50) Google Scholar These cytokines play important roles in the initiation and development of chronic inflammation. IL-8 transcription induced by OxPAPC lasts at least 18 h, with the peak of mRNA expression at approximately 6 h following OxPAPC treatment. In contrast, TNFα-induced IL-8 transcription reaches its peak at 1 h and remains increased during 4 h following treatment.41Yeh M. Gharavi N.M. Choi J. et al.Oxidized phospholipids increase interleukin 8 (IL-8) synthesis by activation of the c-src/signal transducers and activators of transcription (STAT)3 pathway.J Biol Chem. 2004; 279: 30175-30181Crossref PubMed Scopus (113) Google Scholar Unlike classic inflammatory mediators such as LPS and TNFα, the induction of these inflammatory mediator genes by OxPL is achieved through different transcription mechanisms. IL-8 transcription is induced by TNFα mainly through the nuclear factor κB (NFκB) pathway. The activation of IL-8 transcription by OxPL, however, is independent of the NFκB pathway and may be mediated by various pathways that include the c-Src/JAK2/STAT3 pathway,41Yeh M. Gharavi N.M. Choi J. et al.Oxidized phospholipids increase interleukin 8 (IL-8) synthesis by activation of the c-src/signal transducers and activators of transcription (STAT)3 pathway.J Biol Chem. 2004; 279: 30175-30181Crossref PubMed Scopus (113) Google Scholar PPARγ pathway,8Lee H. Shi W. Tontonoz P. et al.Role for peroxisome proliferator-activated receptor alpha in oxidized phospholipid-induced synthesis of monocyte chemotactic protein-1 and interleukin-8 by endothelial cells.Circ Res. 2000; 87: 516-521Crossref PubMed Scopus (275) Google Scholar eNOS/SREBP,42Gharavi N.M. Baker N.A. Mouillesseaux K.P. et al.Role of endothelial nitric oxide synthase in the regulation of SREBP activation by oxidized phospholipids.Circ Res. 2006; 98: 768-776Crossref PubMed Scopus (58) Google Scholar and UPR.22Oskolkova O.V. Afonyushkin T. Leitner A. et al.ATF4-dependent transcription is a key mechanism in VEGF up-regulation by oxidized phospholipids: critical role of oxidized sn-2 residues in activation of unfolded protein response.Blood. 2008; 112: 330-339Crossref PubMed Scopus (87) Google Scholar, 34Gargalovic P.S. Gharavi N.M. Clark M.J. et al.The unfolded protein response is an important regulator of inflammatory genes in endothelial cells.Arterioscler Thromb Vasc Biol. 2006; 26: 2490-2496Crossref PubMed Scopus (315) Google Scholar Src kinases participate in growth factor/cytokine signal transduction pathways that mediate proliferation, survival, differentiation, and apoptosis. OxPAPC activates Src kinase and its downstream effector STAT3, which regulates IL-8 transcription through the binding to a gamma-interferon activation sequence element in the IL-8 promoter.43Gharavi N.M. Alva J.A. Mouillesseaux K.P. et al.Role of the Jak/STAT pathway in the regulation of interleukin-8 transcription by oxidized phospholipids in vitro and in atherosclerosis in vivo.J Biol Chem. 2007; 282: 31460-31468Crossref PubMed Scopus (126) Google Scholar Moreover, the activation of Src kinase by OxPAPC is independent of cAMP/protein kinase A (PKA) pathway used by OxPAPC in activating β1 integrin for monocyte binding mentioned above. Evidence indicates that OxPAPC activates SREBP in human artificial episomal chromosome after 1 h treatment, and the activation persisted for 8 h.31Yeh M. Cole A.L. Choi J. et al.Role for sterol regulatory element-binding protein in activation of endothelial cells by phospholipid oxidation products.Circ Res. 2004; 95: 780-788Crossref PubMed Scopus (88) Google Scholar More investigation provided evidence for the role of endothelial nitric oxide synthase (eNOS) in the activation of SREBP by OxPAPC. OxPAPC treatment of ECs induced a dose- and time-dependent activation of eNOS, and the NOS inhibitor N-nitro-L-arginine-methyl e
Referência(s)