A Lipid Peroxidation-derived Inflammatory Mediator

Cyclooxygenases (COXs) catalyze the conversion of arachidonic acid to eicosanoids, which mediate a variety of biological actions involved in vascular pathophysiology. In the present study, we investigated the role of lipid peroxidation products in the up-regulation of COX-2, an inducible isoform responsible for high levels of prostaglandin production during inflammation and immune responses. COX-2 was found to colocalize with 4-hydroxy-2-nonenal (HNE), a major lipid peroxidation-derived aldehyde, in foamy macrophages within human atheromatous lesions, suggesting that COX-2 expression may be associated with the accumulation of lipid peroxidation products within macrophages. To test the hypothesis that lipid peroxidation products might be involved in the regulation of prostanoid biosynthesis, we conducted a screen of oxidized fatty acid metabolites and found that, among the compounds tested, only HNE showed inducibility of the COX-2 protein in RAW264.7 macrophages. In addition, intraperitoneal administration of HNE resulted in an increase in cell numbers in the peritoneal cavity that was associated with significant increases in the peritoneal and tissue levels of COX-2 in mice. To understand the possible signaling mechanism underlying the inducing effect of HNE on COX-2 up-regulation, we examined the phosphorylation events that may lead to COX-2 induction and found that HNE did not stimulate the induction of nitric oxide synthase and activation of NF-κB but significantly activated p38 mitogen-activated protein kinase and its upstream kinase in RAW264.7 macrophages. Tyrosine kinases, such as the epidermal growth factor-like and Src family tyrosine kinases, appeared to mediate the stabilization of COX-2 mRNA via the p38 mitogen-activated protein kinase pathway. These findings suggest that HNE accumulated in macrophages/foam cells may represent an inflammatory mediator that plays a role in stimulation of the inflammatory response and contributes to the progression of atherogenesis. Cyclooxygenases (COXs) catalyze the conversion of arachidonic acid to eicosanoids, which mediate a variety of biological actions involved in vascular pathophysiology. In the present study, we investigated the role of lipid peroxidation products in the up-regulation of COX-2, an inducible isoform responsible for high levels of prostaglandin production during inflammation and immune responses. COX-2 was found to colocalize with 4-hydroxy-2-nonenal (HNE), a major lipid peroxidation-derived aldehyde, in foamy macrophages within human atheromatous lesions, suggesting that COX-2 expression may be associated with the accumulation of lipid peroxidation products within macrophages. To test the hypothesis that lipid peroxidation products might be involved in the regulation of prostanoid biosynthesis, we conducted a screen of oxidized fatty acid metabolites and found that, among the compounds tested, only HNE showed inducibility of the COX-2 protein in RAW264.7 macrophages. In addition, intraperitoneal administration of HNE resulted in an increase in cell numbers in the peritoneal cavity that was associated with significant increases in the peritoneal and tissue levels of COX-2 in mice. To understand the possible signaling mechanism underlying the inducing effect of HNE on COX-2 up-regulation, we examined the phosphorylation events that may lead to COX-2 induction and found that HNE did not stimulate the induction of nitric oxide synthase and activation of NF-κB but significantly activated p38 mitogen-activated protein kinase and its upstream kinase in RAW264.7 macrophages. Tyrosine kinases, such as the epidermal growth factor-like and Src family tyrosine kinases, appeared to mediate the stabilization of COX-2 mRNA via the p38 mitogen-activated protein kinase pathway. These findings suggest that HNE accumulated in macrophages/foam cells may represent an inflammatory mediator that plays a role in stimulation of the inflammatory response and contributes to the progression of atherogenesis. Atherosclerosis is a disorder of lipid metabolism as well as a chronic inflammatory disease. Monocyte-derived macrophages play a prominent role in the formation and progression of atherosclerotic plaque, particularly after their transformation into foam cells. When activated by inflammatory stimuli, the macrophages synthesize and secrete various mediators, including cytokines, prothrombotic substances, and eicosanoids that cause the clinical manifestations and acute clinical complications of atherosclerosis. The eicosanoids derived from the metabolism of arachidonate have been extensively investigated because several studies have focused on their close relation to atherogenesis (1FitzGerald G.A. Austin S. Egan K. Cheng Y. Pratico D. Ann. Med. 2000; 32: 21-26PubMed Google Scholar, 2Gimbrone Jr., M.A. Topper J.N. Nagel T. Anderson K.R. Garcia-Cardena G. Ann. N. Y. Acad. Sci. 2000; 902: 230-239Crossref PubMed Scopus (716) Google Scholar). In macrophages, as well as in other cell types, arachidonate metabolites are synthesized by the cyclooxygenase enzyme. Presently, two isoforms of cyclooxygenase have been identified: cyclooxygenase-1 (COX-1), 1The abbreviations used are: COX, cyclooxygenase; MAPK, mitogen-activated protein kinase; NF-κB, nuclear factor-κB; IκB, inhibitor-κB; LDL, low density lipoprotein; HNE, 4-hydroxy-2-nonenal; PBS, phosphate-buffered saline; LPS, lipopolysaccharide; EGFR, EGFR, epidermal growth factor receptor; PDGFR, platelet-derived growth factor receptor; GAPDH, glyceraldehyde-3-phosphate dehydrogenase; MKK, mitogen-activated protein kinase kinase; iNOS, inducible nitric oxide synthase. which is the constitutive form, and cyclooxygenase-2 (COX-2), which is the inducible form. COX-1, with an mRNA transcript of 2.8–3.0 kb, is present under normal conditions in most tissues and is responsible for housekeeping functions. On the other hand, COX-2, with an mRNA transcript of 4.0–4.5 kb, is not normally present under basal conditions or is present in very low amounts. However, COX-2 is rapidly induced by various stimuli, including proinflammatory cytokines such as interleukin-1β and tumor necrosis factor-α, growth factors, and tumor promoters, to result in prostaglandin synthesis associated with inflammation and carcinogenesis (3FitzGerald G.A. Nat. Rev. 2003; 2: 879-890Google Scholar). In macrophages, COX-2 expression appears to be mediated through both mitogen-activated protein kinase (MAPK) and nuclear factor-κB (NF-κB) signaling pathways (4Hwang D. Jang B.C. Yu G. Boudreau M. Biochem. Pharmacol. 1997; 54: 87-96Crossref PubMed Scopus (235) Google Scholar). Several lines of evidence indicate that the oxidative modification of protein and the subsequent accumulation of the modified proteins have been found in cells during aging, oxidative stress, and in various pathological states including premature diseases, muscular dystrophy, rheumatoid arthritis, and atherosclerosis (5Shacter E. Drug. Metab. Rev. 2000; 32: 307-326Crossref PubMed Scopus (664) Google Scholar, 6Stadtman E.R. Levine R.L. Ann. N. Y. Acad. Sci. 2000; 899: 191-208Crossref PubMed Scopus (977) Google Scholar). The important agents that give rise to the modification of a protein may be represented by reactive aldehydic intermediates such as ketoaldehydes, 2-alkenals, and 4-hydroxy-2-alkenals (7Uchida K. Free Radic. Biol. Med. 2000; 28: 1685-1696Crossref PubMed Scopus (536) Google Scholar). These reactive aldehydes are considered important mediators of cell damage because of their ability to covalently modify biomolecules that can disrupt important cellular functions and can cause mutations (8Esterbauer H. Schauer R.J. Zollner H. Free Radic. Biol. Med. 1991; 11: 81-128Crossref PubMed Scopus (5936) Google Scholar, 9Uchida K. Prog. Lipid. Res. 2003; 42: 318-343Crossref PubMed Scopus (976) Google Scholar). Furthermore, the adduction of aldehydes to apolipoprotein B in low density lipoproteins (LDL) has been strongly implicated in the mechanism by which LDL is converted to an atherogenic form that is taken up by macrophages, leading to the formation of foam cells (10Steinberg D. Parthasarathy S. Carew T.E. Khoo J.C. Witztum J.L. N. Engl. J. Med. 1989; 320: 915-924Crossref PubMed Google Scholar, 11Steinberg D. Adv. Exp. Med. Biol. 1995; 369: 39-48Crossref PubMed Scopus (165) Google Scholar). 4-Hydroxy-2-nonenal (HNE), among the reactive aldehydes, is a major product of lipid peroxidation and is believed to be largely responsible for the cytopathological effects observed during oxidative stress (8Esterbauer H. Schauer R.J. Zollner H. Free Radic. Biol. Med. 1991; 11: 81-128Crossref PubMed Scopus (5936) Google Scholar, 9Uchida K. Prog. Lipid. Res. 2003; 42: 318-343Crossref PubMed Scopus (976) Google Scholar). Atherogenesis involves several aspects of chronic inflammation and wound healing. Indeed, the atheroma is considered a special case of tissue response to injury. Injurious stimuli may include lipoproteins trapped within lesions where protein and lipid moieties have undergone oxidative modifications. In a recent study, oxidized LDL components were shown to activate CD36, an important scavenger receptor, mediating the uptake of oxidized LDL (12Podrez E.A. Poliakov E. Shen Z. Zhang R. Deng Y. Sun M. Finton P.J. Shan L. Gugiu B. Fox P.L. Hoff H.F. Salomon R.G. Hazen S.L. J. Biol. Chem. 2002; 277: 38503-38516Abstract Full Text Full Text PDF PubMed Scopus (389) Google Scholar, 13Ishii T. Itoh K. Ruiz E. Leake D.S. Unoki H. Yamamoto M. Mann G.E. Circ. Res. 2004; 94: 609-616Crossref PubMed Scopus (360) Google Scholar). These findings suggest that oxidized LDL contains a pro-atherogenic molecule that plays a role in foam cell formation and the pathogenesis of atherosclerosis. In view of the observation that increased eicosanoid production is closely associated with atherogenesis (1FitzGerald G.A. Austin S. Egan K. Cheng Y. Pratico D. Ann. Med. 2000; 32: 21-26PubMed Google Scholar, 2Gimbrone Jr., M.A. Topper J.N. Nagel T. Anderson K.R. Garcia-Cardena G. Ann. N. Y. Acad. Sci. 2000; 902: 230-239Crossref PubMed Scopus (716) Google Scholar), we hypothesized that an oxidized LDL component might be involved in the up-regulation of the prostaglandin biosynthesis. Even human atherosclerotic lesions have been shown to a of oxidized LDL we their in macrophages. In the present study, we have that COX-2 with HNE in foam cells within atheromatous the effect of the oxidized fatty acid metabolites on COX-2 induction in RAW264.7 macrophages and HNE as the of COX-2 the of HNE in COX-2 expression is by that COX-2 is in with a mechanism involved in the COX-2 expression by HNE is was from was synthesized by the of with by L. R. Scopus Google Scholar). and were from and were from The p38 was from The tyrosine kinase and were from synthesis was from was from and were from was the protein from cell RAW264.7 was by The cells were in modified with and in an of and cells were to in modified and cells were with phosphate-buffered and with protein of protein were with for PubMed Scopus Google Scholar). The were on to a with in for and with the with were for with to in were in was used for and was with The was by the The was with of and an the synthesis were of in of of and and of The conditions COX-2, for for and for for GAPDH, for for and for for by for The were COX-2, and GAPDH, and cells were with HNE for to COX-2 mRNA The was to with or an cells were for was examined by The levels of COX-2 mRNA were for the of the were of and in with a were of and the as and a intraperitoneal of HNE of an of were by and after the the were with of The peritoneal cavity was and the and was with peritoneal cells were in and for the cells were by with and cells were with and of COX-2, tissues from the and were in in to and used for by an with after with and and were or the of normal of showed or responses. of COX-2 and HNE in were from with atherosclerosis and used for and was after family in with the of of from case were in in and were from and used for or and the were for with in PBS, and for in for The tissues were with in for and for with a a of a of or the a of was the to the was used as the and was used as the from which the were as The of HNE and COX-2 were by with and for of COX-2 with HNE in evidence for the of lipid peroxidation products in COX-2 in we examined the of COX-2 and a lipid peroxidation HNE, in human atherosclerotic The or COX-2 and HNE not in and the atherosclerotic both COX-2 and HNE in the of foamy macrophages and These macrophages were by and on not or was found that both COX-2 and HNE with other cell types, but the were shown in foam cells. product were in with of the These suggest that COX-2 expression may be associated with the accumulation of lipid peroxidation products within macrophages. of HNE as a COX-2 test lipid peroxidation products might be involved in regulation of prostaglandin biosynthesis, we conducted a screen of oxidized fatty acid RAW264.7 macrophages were for with of the and COX-2 induction was examined by an among the oxidized only HNE showed inducibility of the COX-2 protein an of HNE, did not effect on COX-2 These and the observation that COX-2 with HNE in human atherosclerotic lesions suggest that HNE might be involved in COX-2 induction in macrophages. HNE COX-2 in RAW264.7 examined HNE for an effect on COX-2 When the cells were with HNE, increases in COX-2 protein levels in response to HNE were observed by the of the was effects of HNE were the of induction and the COX-2 protein was induced in the of regulation of was in the effect of HNE on the COX-2 protein was with levels of COX-2 The increase in the COX-2 with a rise in the COX-2 protein has been shown that oxidized LDL including HNE, activate CD36, an important scavenger receptor, mediating the uptake of oxidized LDL T. Itoh K. Ruiz E. Leake D.S. Unoki H. Yamamoto M. Mann G.E. Circ. Res. 2004; 94: 609-616Crossref PubMed Scopus (360) Google Scholar). with COX-2 expression was associated with the expression of other such as These suggest that HNE may represent an inflammatory mediator that is of inducing several pro-atherogenic in macrophages. COX-2 in with HNE is of inducing COX-2 expression in were intraperitoneal with HNE for and in cell numbers and COX-2 levels in the peritoneal cavity were shown in the showed a increase in cell numbers in the peritoneal increase was because of HNE, as did not a cellular cellular was associated with the increased expression of COX-2 in peritoneal macrophages we examined COX-2 levels in the tissues and from with HNE and found that COX-2 was significantly induced by HNE in tissues the induction of COX-2 in the tissues from with HNE HNE COX-2 through an has been shown that nitric oxide may increase prostaglandin synthesis by activation of the COX-2 protein M. M. Acad. Sci. S. PubMed Scopus Google Scholar, D. J.L. K. Acad. Sci. S. PubMed Scopus Google Scholar, D. K. J.L. J. PubMed Scopus Google Scholar, D. K. J. J.L. J. 1995; PubMed Scopus Google Scholar, Circ. 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Exp. 2003; PubMed Scopus Google Scholar). to NF-κB is involved in COX-2 we examined NF-κB activation in RAW264.7 macrophages with shown in induced of the and significantly the nuclear of NF-κB significant in and NF-κB levels was observed in the cells and appears that HNE COX-2 expression through an of Tyrosine in COX-2 understand the possible signaling mechanism underlying the inducing effect of HNE on COX-2 up-regulation, we examined the phosphorylation events that may lead to COX-2 of tyrosine was by the that a tyrosine kinase significantly COX-2 induction a of protein tyrosine To HNE can activate cellular protein kinases, the cells with HNE and the tyrosine phosphorylation of cellular proteins were by with shown in several proteins with of and were the proteins after with The increase in tyrosine phosphorylation was within during HNE and up to after the In addition, tyrosine phosphorylation was significantly by and the of the Src family and tyrosine kinases, B and the increase in tyrosine phosphorylation to that the activation of protein tyrosine is of the upstream of COX-2 induction in cells. In with the of the Src family and tyrosine significantly COX-2 expression is that protein may be involved in the induction of COX-2 by of Tyrosine in p38 of COX-2 has been shown that p38 plays a role in COX-2 induction (4Hwang D. Jang B.C. Yu G. Boudreau M. Biochem. Pharmacol. 1997; 54: 87-96Crossref PubMed Scopus (235) Google Scholar). In addition, we have shown that HNE the p38 in cells T. Y. T. K. Biochem. 2002; PubMed Scopus Google Scholar). we examined the of tyrosine in COX-2 expression through the p38 pathway. shown in after stimulation with HNE, p38 was rapidly and strongly within and phosphorylation was after which is an upstream kinase of p38 MAPK, was by HNE and phosphorylation was with the p38 HNE activated kinase; a of kinase and mitogen-activated protein kinase was not by the HNE not The of a p38 in the COX-2 expression was by the observation that a p38 significantly COX-2 expression To the possible tyrosine and MAPK, the effect of of the Src family and tyrosine phosphorylation of p38 was shown in both tyrosine kinase and significantly the phosphorylation of p38 The result that HNE the p38 via the Src family and tyrosine p38 COX-2 mRNA levels by a in mRNA G.A. J. Biol. Chem. 2000; Full Text Full Text PDF PubMed Scopus Google Scholar, J.L. M. J. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar, M. K.R. G. J. Biol. 2000; PubMed Scopus Google Scholar), was hypothesized that HNE induced COX-2 expression by the of COX-2 mRNA via the p38 pathway. To the of tyrosine in COX-2 mRNA we COX-2 mRNA levels by of an M. K.R. G. J. Biol. 2000; PubMed Scopus Google Scholar, M. M. J. Biol. PubMed Scopus Google Scholar). In because of the of by the synthesis subsequent mRNA levels on the the increase in COX-2 mRNA is to stabilization of mRNA and is mediated by the p38 COX-2 mRNA levels rapidly with p38 shown in in the of the p38 the COX-2 mRNA a by In the of the p38 strongly COX-2 mRNA by suggesting that COX-2 expression resulted from the stabilization of COX-2 mRNA that is mediated by the p38 signaling pathway. Furthermore, the Src family and tyrosine kinase that p38 phosphorylation significantly the COX-2 mRNA B and the tyrosine kinases, such as the and Src family tyrosine kinases, may mediate the stabilization of COX-2 mRNA via the p38 pathway. The of lipid peroxidation products has been in chronic human diseases, including atherosclerosis and K. Prog. Lipid. Res. 2003; 42: 318-343Crossref PubMed Scopus (976) Google Scholar). The of atherosclerotic lesions from the human that HNE was associated with macrophages is from in studies that of the major cell within the atherosclerotic lesions are of the of LDL T.E. D. Acad. Sci. S. PubMed Scopus Google Scholar, PubMed Google Scholar, Parthasarathy S. Leake D.S. Witztum J.L. D. Acad. Sci. S. PubMed Scopus Google Scholar, L. H. J. PubMed Scopus Google Scholar, J. Biol. PubMed Scopus Google the we observed are to the cellular of LDL by macrophages, and cells. The oxidized LDL may be taken up by cells and may be the of the that in atherosclerotic In addition, observed in atherosclerotic lesions the of lipid peroxidation products that been taken up by macrophages and are present within the cell in S. S. Witztum J.L. PubMed Scopus Google Scholar). to the that the lipid adduction proteins to in the accumulation of in macrophages. On the other hand, COX-2 expression or prostaglandin in atherosclerotic lesions has been S. J. Full Text Full Text PDF PubMed Scopus Google that human atheromatous lesions COX-2, with macrophages of the and lipid The of lipid peroxidation products in COX-2 was by that, within atheromatous lesions, COX-2 appeared to colocalize with HNE in foam cells To test the hypothesis that lipid peroxidation products may be involved in the up-regulation of prostaglandin biosynthesis, we the effect of oxidized fatty acid metabolites on COX-2 induction in RAW264.7 macrophages and HNE as an of COX-2 expression HNE is a major product of lipid peroxidation by oxidative stress that is by of fatty such as and arachidonic two fatty in human cells (8Esterbauer H. Schauer R.J. Zollner H. Free Radic. Biol. Med. 1991; 11: 81-128Crossref PubMed Scopus (5936) Google Scholar). has been shown that high of HNE can be during in of LDL (8Esterbauer H. Schauer R.J. Zollner H. Free Radic. Biol. Med. 1991; 11: 81-128Crossref PubMed Scopus (5936) Google Scholar, H. M. G. G. G. Chem. Res. PubMed Scopus Google Scholar, H. J. H. G. Free Radic. Biol. Med. PubMed Scopus Google Scholar). levels of HNE have been in tissues and the cellular of HNE from to (8Esterbauer H. Schauer R.J. Zollner H. Free Radic. Biol. Med. 1991; 11: 81-128Crossref PubMed Scopus (5936) Google Scholar, 9Uchida K. Prog. Lipid. Res. 2003; 42: 318-343Crossref PubMed Scopus (976) Google Scholar). The of in cells is high with the of agents that cells may under However, under oxidative stress HNE can of to both in and in (8Esterbauer H. Schauer R.J. Zollner H. Free Radic. Biol. Med. 1991; 11: 81-128Crossref PubMed Scopus (5936) Google Scholar, 9Uchida K. Prog. Lipid. Res. 2003; 42: 318-343Crossref PubMed Scopus (976) Google Scholar, Med. 2003; PubMed Scopus Google an cellular because of its high (8Esterbauer H. Schauer R.J. Zollner H. Free Radic. Biol. Med. 1991; 11: 81-128Crossref PubMed Scopus (5936) Google Scholar). in to and in the of HNE can up to in M. M. N. N. M. N. K. J. Google Scholar, T. K. Y. K. T. K. Res. Chem. Pharmacol. Google Scholar, R.G. J. Zhang L. Res. 2000; Google Scholar, M. E. Chem. Biol. PubMed Scopus Google Scholar). of HNE have been to in cells are to agents that lipid peroxidation R.J. M.A. K. J. 1997; PubMed Scopus Google Scholar). the of HNE in may be for to play a role in most of the that have been shown to in is of to that other lipid peroxidation an to that of HNE, were on COX-2 The of to COX-2 is particularly because HNE has been to be reactive HNE the and as well as and proteins T. J. Biol. Chem. 2003; Full Text Full Text PDF PubMed Scopus Google Scholar). the that may be a cellular of HNE that may or lead to COX-2 is to the molecule that pathways leading to COX-2 to the cellular of HNE, the of that the Src family and tyrosine might be for p38 activation The findings that HNE of J. G. R. J. PubMed Scopus Google Scholar, M.A. Google Scholar), HNE cell growth and cell by M. T. K. K. J. Sci. PubMed Google Scholar), and HNE of the kinase of K. Y. M. M. H. N. 2003; PubMed Scopus Google suggest that HNE, from oxidized LDL or the cells during oxidative stress, may with tyrosine Indeed, oxidized LDL not have been shown to the formation of and as by the in and of HNE protein with protein and by the of by the J. G. R. J. PubMed Scopus Google Scholar, R. N. G. B. Parthasarathy S. PubMed Scopus Google Scholar). oxidized of and by HNE is associated with activation of the tyrosine kinase and with of the and the subsequent of These effects are by the of HNE to cell which both and activation of the On the other hand, studies have evidence the activation of tyrosine to p38 Z. T. G. E. J. 2000; PubMed Scopus Google Scholar). However, is mechanism as to the Src family and tyrosine may the of p38 The that activation of p38 in cells by and that the Src family and tyrosine may the of p38 through signaling is evidence that p38 is important for both COX-2 and mRNA has shown that the p38 plays a role in the mechanism of COX-2 expression in Z. J. Pharmacol. Exp. 2003; PubMed Scopus Google Scholar). observed that the p38 activated by HNE its by the of COX-2 mRNA in RAW264.7 macrophages a we found that, was by the of the of COX-2 rapidly the p38 was by the of other possible p38 that to the COX-2 were not in study, that p38 is to the of the COX-2 transcript in cells to On the other hand, the NF-κB is major stress response signaling pathway. In and the COX-2 has factors, including NF-κB in the of the H. Y. T. J. Biol. Chem. 1995; Full Text Full Text PDF PubMed Scopus Google Scholar, Y. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar, J. Biol. Chem. 2000; Full Text Full Text PDF PubMed Scopus Google Scholar), and the of the activation of NF-κB to the expression of COX-2 in macrophages has been (4Hwang D. Jang B.C. Yu G. Boudreau M. Biochem. Pharmacol. 1997; 54: 87-96Crossref PubMed Scopus (235) Google Scholar). The NF-κB has been implicated in the expression of COX-2 by tumor necrosis factor-α, and interleukin-1β in cells Jr., J. Biol. Chem. 1997; Full Text Full Text PDF PubMed Scopus Google and J. S. J. S. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar). The present showed that induced of the and significantly the nuclear of NF-κB In to the COX-2 significant in and NF-κB levels was observed in the macrophages and in with COX-2 expression was not associated with the induction of the that HNE COX-2 NF-κB activation is in to the that NF-κB activation is for COX-2 induction in macrophages D. J. Biol. Chem. 2000; Full Text Full Text PDF PubMed Scopus Google Scholar, E. K. H. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar, Z. J. Pharmacol. Exp. 2003; PubMed Scopus Google Scholar). In we showed that HNE strongly induced COX-2 expression in macrophages. a of a the oxidative modification of LDL and activation of the inflammatory of macrophages. The observed effect be in where close macrophages and oxidized might result in the of an inflammatory with a cell to tissue may represent an important in an in the of transformation into the foam cells the fatty a of atherosclerosis. with