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Phosphatidylinositol 3-Kinase Is Involved in the Induction of Macrophage Growth by Oxidized Low Density Lipoprotein*

Open AccessPublished:February 27, 1998DOI:https://doi.org/10.1074/jbc.273.9.4915
      Early atherosclerotic lesions are characterized by the presence of cholesterol-rich, macrophage-derived foam cells. It has recently been shown that macrophage proliferation occurs during the development of early lesions and that oxidized low density lipoprotein (LDL) stimulates macrophage growth. Possible mechanisms for this induction of macrophage growth include potentiation of mitogenic signal transduction by a component of oxidized LDL following internalization and degradation, interaction with integral plasma membrane proteins coupled to signaling pathways, or direct or indirect activation of growth factor receptors on the cell surface (e.g. GM-CSF receptor) through an autocrine/paracrine mechanism. The present study was undertaken to characterize some of the early intracellular signaling events by which oxidized LDL mediates macrophage cell growth. Extensively oxidized LDL increased protein-tyrosine phosphorylation and caused a 2-fold increase in phosphatidylinositol (PI) 3-kinase activity in phorbol ester-pretreated THP-1 cells (a human monocyte-like cell line). Similar concentrations of native LDL had no effect. Oxidized LDL also stimulated growth of resident mouse peritoneal macrophages, and this effect was reduced by 40–50% in cells treated with PI 3-kinase inhibitors (100 nm wortmannin or 20 μmLY294002). These results suggest that PI 3-kinase mediates part of the mitogenic effect of oxidized LDL, but parallel pathways involving other receptors and signal transduction pathways are likely also involved.
      Several lines of evidence have implicated oxidized low density lipoprotein (LDL)
      The abbreviations used are: LDL, low density lipoprotein; GM-CSF, granulocyte-macrophage colony-stimulating factor; PI, phosphatidylinositol; PKC, protein kinase C; XTT, 2,3-bis[2-methoxy-4-nitro-5-sulfophenyl]-2H-tetrazolium-5-carboxanilide; MAP, mitogen-activated protein; FBS, fetal bovine serum; LPS, lipopolysaccharide; PMA, phorbol myristate acetate; PBS, phosphate-buffered saline.
      1The abbreviations used are: LDL, low density lipoprotein; GM-CSF, granulocyte-macrophage colony-stimulating factor; PI, phosphatidylinositol; PKC, protein kinase C; XTT, 2,3-bis[2-methoxy-4-nitro-5-sulfophenyl]-2H-tetrazolium-5-carboxanilide; MAP, mitogen-activated protein; FBS, fetal bovine serum; LPS, lipopolysaccharide; PMA, phorbol myristate acetate; PBS, phosphate-buffered saline.
      in the pathogenesis of atherosclerosis, including the demonstration that oxidatively modified LDL exists in the arterial intima in vivo (
      • Palinski W.
      • Rosenfeld M.E.
      • Ylä-Herttuala S.
      • Gurtner G.C.
      • Socher S.S.
      • Butler S.W.
      • Parthasarathy S.
      • Carew T.E.
      • Steinberg D.
      • Witztum J.L.
      ,
      • Ylä-Herttuala S.
      • Palinski W.
      • Rosenfeld M.E.
      • Parthasarathy S.
      • Carew T.E.
      • Butler S.
      • Witztum J.L.
      • Steinberg D.
      ) and that antioxidant drugs can retard atherogenesis in some animal models (
      • Carew T.E.
      • Schwenke D.C.
      • Steinberg D.
      ,
      • Kita T.
      • Nagano Y.
      • Yokode M.
      • Ishii K.
      • Kume N.
      • Ooshima A.
      • Yoshida H.
      • Kawai C.
      ,
      • Björkhem I.
      • Henriksson-Freyschuss A.
      • Breuer O.
      • Diczfalusy U.
      • Berglund L.
      • Henriksson P.
      ,
      • Sparrow C.P.
      • Doebber T.W.
      • Olszewski J.
      • Wu M.S.
      • Ventre J.
      • Stevens K.A.
      • Chao Y.-S.
      ,
      • Sasahara M.
      • Raines E.W.
      • Chait A.
      • Carew T.E.
      • Steinberg D.
      • Wahl P.W.
      • Ross R.
      ). Oxidized LDL has been shown to have many potentially atherogenic actions in vitro (
      • Steinberg D.
      • Parthasarathy S.
      • Carew T.E.
      • Khoo J.C.
      • Witztum J.L.
      ), but its role in foam cell formation is of particular relevance to early stages of atherogenesis (
      • Fowler S.
      • Shio H.
      • Haley W.J.
      ,
      • Ross R.
      ,
      • Gerrity R.G.
      ,
      • Gerrity R.G.
      ). Foam cells are lipid-laden macrophages and are derived from blood-borne monocytes that have been recruited to sites of predilection of atherosclerosis by overexpression of endothelial adhesion molecules and by local release of chemotactic factors (
      • Cybulsky M.I.
      • Gimbrone M.A.
      ,
      • Kume N.
      • Cybulsky M.
      • Gimbrone M.A.
      ). Both of these effects have been associated with oxidized LDL (
      • Quinn M.T.
      • Parthasarathy S.
      • Steinberg D.
      ,
      • Cushing S.D.
      • Berliner J.A.
      • Valente A.J.
      • Territo M.C.
      • Navab M.
      • Parhami F.
      • Gerrity R.
      • Schwartz C.J.
      • Fogelman A.M.
      ,
      • Berliner J.A.
      • Territo M.C.
      • Sevanian A.
      • Ramin S.
      • Kim J.A.
      • Bamshad B.
      • Esterson M.
      • Fogelman A.M.
      ,
      • Rajavashisth T.B.
      • Andalibi A.
      • Territo M.C.
      • Berliner J.A.
      • Navab M.
      • Fogelman A.M.
      • Lusis A.J.
      ,
      • Berliner J.A.
      • Schwartz D.S.
      • Territo M.C.
      • Andalibi A.
      • Almada L.
      • Lusis A.J.
      • Quismorio D.
      • Fang Z.P.
      • Fogelman A.M.
      ,
      • Kim J.
      • Territo M.
      • Wayner E.
      • Carlos T.
      • Parhami F.
      • Smith C.
      • Haberland M.
      • Fogelman A.
      • Berliner J.
      ,
      • Schwartz D.
      • Andalibi A.
      • Chaverri-Almada L.
      • Berliner J.
      • Kirchgessner T.
      • Fang Z.-T.
      • Tekamp-Olson P.
      • Lusis A.
      • Fogelman A.
      • Territo M.
      ).
      An additional mechanism that would increase the number of macrophages in the arterial intima at sites of lesion formation is cell proliferation. Immunocytochemical studies of human atherosclerotic lesions have shown that macrophages are the predominant cell type expressing proliferating cell nuclear antigen in lesions, even in lesions containing cells derived mainly from smooth muscle cells (
      • Katsuda S.
      • Coltrera M.D.
      • Ross R.
      • Gown A.M.
      ,
      • Rekhter M.D.
      • Gordon D.
      ). Oxidized LDL has recently been shown to be mitogenic for mouse peritoneal macrophages as well as human monocyte-derived macrophages (
      • Sakai M.
      • Miyazaki A.
      • Hakamata H.
      • Sasaki T.
      • Yui S.
      • Yamazaki M.
      • Shichiri M.
      • Horiuchi S.
      ,
      • Yui S.
      • Sasaki T.
      • Miyazaki A.
      • Horiuchi S.
      • Yamazaki M.
      ). In these studies, the mitogenic effect of oxidized-LDL was attributed to lysophosphatidylcholine and was dependent on scavenger receptor-mediated uptake of the oxidized LDL particles (
      • Sakai M.
      • Miyazaki A.
      • Hakamata H.
      • Kodama T.
      • Suzuki H.
      • Kobori S.
      • Shichiri M.
      • Horiuchi S.
      ). Macrophage growth was inhibited with anti-GM-CSF antibody, suggesting that oxidized LDL may induce secretion of GM-CSF, leading to autocrine or paracrine growth stimulation (
      • Sakai M.
      • Miyazaki A.
      • Hakamata H.
      • Sasaki T.
      • Yui S.
      • Yamazaki M.
      • Shichiri M.
      • Horiuchi S.
      ). Oxidized LDL is also mitogenic for bovine vascular smooth muscle cells (
      • Heery J.M.
      • Kozak M.
      • Stafforini D.M.
      • Jones D.A.
      • Zimmerman G.A.
      • McIntyre T.M.
      • Prescott S.M.
      ). In these cells, the mitogenic effect was blocked with platelet-activating factor receptor antagonists, suggesting that oxidized LDL may also stimulate growth directly through platelet-activating factor receptor activation. Oxidized LDL has been found to increase phosphoinositide turnover in vascular smooth muscle cells (
      • Resink T.J.
      • Tkachuk V.A.
      • Bernhardt J.
      • Bühler F.R.
      ), which would be consistent with an effect mediated by the platelet-activating factor receptor, a G-protein-linked receptor that activates phosphatidylinositol-specific phospholipase C (
      • Venable M.E.
      • Zimmerman G.A.
      • McIntyre T.M.
      • Prescott S.M.
      ).
      Growth factor receptor-mediated signaling commonly involves the activation of mitogen-activated protein (MAP) kinase, protein-tyrosine kinases, and phosphatidylinositol (PI) 3-kinase (
      • Claus R.
      • Fyrnys B.
      • Deigner H.P.
      • Wolf G.
      ,
      • Miki S.
      • Tsukada S.
      • Nakamura Y.
      • Aimoto S.
      • Hojo H.
      • Sato B.
      • Yamamoto M.
      • Miki Y.
      ). Exposure of transformed macrophage cell lines to oxidized LDL or acetyl LDL has been reported to lead to the activation of MAP kinase (
      • Deigner H.
      • Claus R.
      ,
      • Kusuhara M.
      • Chait A.
      • Cader A.
      • Berk B.C.
      ), protein kinase C (PKC) (
      • Claus R.
      • Fyrnys B.
      • Deigner H.P.
      • Wolf G.
      ), and the cytoplasmic tyrosine kinase p53/p56 Lyn (
      • Miki S.
      • Tsukada S.
      • Nakamura Y.
      • Aimoto S.
      • Hojo H.
      • Sato B.
      • Yamamoto M.
      • Miki Y.
      ). The objective of the present study was to determine if oxidized LDL leads to increased protein-tyrosine phosphorylation and PI 3-kinase activation in macrophages and to define the role of PI 3-kinase in the mitogenic activity of oxidized LDL.

      DISCUSSION

      Oxidized LDL has recently been shown to be mitogenic toward several types of cells including murine peritoneal macrophages, human monocyte-derived macrophages, and vascular smooth muscle cells (
      • Sakai M.
      • Miyazaki A.
      • Hakamata H.
      • Sasaki T.
      • Yui S.
      • Yamazaki M.
      • Shichiri M.
      • Horiuchi S.
      ,
      • Yui S.
      • Sasaki T.
      • Miyazaki A.
      • Horiuchi S.
      • Yamazaki M.
      ,
      • Heery J.M.
      • Kozak M.
      • Stafforini D.M.
      • Jones D.A.
      • Zimmerman G.A.
      • McIntyre T.M.
      • Prescott S.M.
      ). In macrophages, the mitogenic effect has been attributed to lysophosphatidylcholine and is reported to require scavenger receptor-mediated internalization of oxidized LDL (
      • Sakai M.
      • Miyazaki A.
      • Hakamata H.
      • Kodama T.
      • Suzuki H.
      • Kobori S.
      • Shichiri M.
      • Horiuchi S.
      ). In smooth muscle cells, the mitogenic effect was found to be mediated by oxidized phospholipids that interacted with the platelet-activating factor receptor (
      • Heery J.M.
      • Kozak M.
      • Stafforini D.M.
      • Jones D.A.
      • Zimmerman G.A.
      • McIntyre T.M.
      • Prescott S.M.
      ). It is not clear whether the divergent conclusions from these studies can be explained by oxidized LDL acting through different pathways in smooth muscle cells and macrophages, or if both lysophosphatidylcholine and oxidized phospholipids can activate similar signaling pathways leading to mitogenesis in these cells.
      The downstream signaling pathways involved in the mitogenic effect of oxidized LDL have not yet been defined. The objective of the present study was to examine the intracellular signaling pathways that may be involved in the induction of macrophage growth by oxidized LDL. The results show that oxidized LDL induces tyrosine phosphorylation of several different proteins in THP-1 macrophages. The main substrates detected have apparent molecular masses of 55–65, 85, 100, and 110 kDa. Maximal phosphorylation of the 55–65-kDa proteins was noted 5 min after addition of oxidized LDL, whereas the higher molecular mass proteins showed maximal phosphorylation after 10 min. The activation of PI 3-kinase by oxidized LDL was concentration- and time-dependent. Moreover, there was a 40–50% decrease in oxidized LDL-induced growth in macrophages pretreated with PI 3-kinase inhibitors, indicating that pathways dependent on PI 3-kinase account for at least 40% of this effect.
      The findings of this study are consistent with previous evidence supporting a role for PI 3-kinase in mitogenic signaling. For example, Iwama et al. have shown that association of PI 3-kinase with the platelet-derived growth factor receptor of vascular smooth muscle cells appears to be necessary for platelet-derived growth factor-induced cellular mitogenesis (
      • Iwama A.
      • Sawamura M.
      • Nara Y.
      • Yamori Y.
      ). Yusoff et al.concluded that PI 3-kinase activation may be involved in growth stimulation of bone marrow-derived macrophage by hematopoietic growth factors CSF-1 and GM-CSF (
      • Yusoff P.
      • Hamilton J.
      • Nolan R.
      • Phillips W.
      ). In these studies, CSF-1 and GM-CSF stimulated a dose-dependent activation of PI 3-kinase, whereas concanavalin A, PMA, and formyl-methionyl-leucyl-phenylalanine had no mitogenic activity and did not significantly increase PI 3-kinase activity.
      Several other studies have also shown that incubation of macrophages with modified LDL leads to rapid tyrosine phosphorylation of several intracellular proteins, including a member of the Src tyrosine kinase family, p53/p56 Lyn (
      • Miki S.
      • Tsukada S.
      • Nakamura Y.
      • Aimoto S.
      • Hojo H.
      • Sato B.
      • Yamamoto M.
      • Miki Y.
      ). Activated tyrosine kinases such as p53/p56 Lyn have been shown to physically interact with and activate PI 3-kinase in human monocytes and B-lymphocytes (
      • Herrera-Velit P.
      • Reiner N.E.
      ,
      • Yamanashi Y.
      • Fukui Y.
      • Wongsasant B.
      • Kinoshita Y.
      • Ichimori Y.
      • Toyoshima K.
      • Yamamoto T.
      ). Association of intracellular PI 3-kinase with activated tyrosine kinases is thought to be mediated by either SH3 domains of tyrosine kinases (
      • Plieman C.M.
      • Clark M.R.
      • Timson L.K.
      • Winitz S.
      • Coggeshell K.M.
      • Johnson G.L.
      • Shaw A.S.
      • Cambier J.C.
      ) or via SH2 domains of the p85 regulatory subunit of PI 3-kinase (
      • Van der Greer P.
      • Hunter T.
      • Lindberg R.
      ), leading to increased PI 3-kinase activity. It has been suggested that association with tyrosine kinases may account for PI 3-kinase activation (
      • Herrera-Velit P.
      • Reiner N.E.
      ), but it is not clear if phosphorylation of the p85 subunit of PI 3-kinase is required for its activation. Several potential phosphorylation sites are present in the p85 subunit (
      • Fry M.
      ), but PI 3-kinase activation can occur without SH2 domain phosphorylation of this subunit (
      • Van der Greer P.
      • Hunter T.
      • Lindberg R.
      ). The results in Fig. 1 indicate an apparent increase in protein-tyrosine phosphorylation in the 85-kDa region of whole cell lysates after exposure of cells to oxidized LDL, but there was no evidence of phosphorylation of the p85 band in immunoprecipitated PI 3-kinase (data not shown).
      Although the findings of this study indicate that the growth-promoting effects of oxidized LDL are PI 3-kinase-dependent, it is likely that additional pathways independent of PI 3-kinase are also involved. One potential target for oxidized LDL-induced mitogenic signaling is PKC. Sakai and colleagues have suggested a role for PKC in oxidized LDL-induced mitogenesis because they found that exposure of murine resident peritoneal macrophages to oxidized LDL results in rapid calcium influx and a sustained increase in intracellular calcium concentrations (
      • Sakai M.
      • Miyazaki A.
      • Hakamata H.
      • Sasaki T.
      • Yui S.
      • Yamazaki M.
      • Shichiri M.
      • Horiuchi S.
      ). Exposure of vascular smooth muscle cells to oxidized LDL has also been shown to increase PKC activity as well as to enhance platelet-derived growth factor-AA production, platelet-derived growth factor receptor mRNA expression, and DNA synthesis (
      • Chai Y.-C.
      • Howe P.H.
      • DiCorleto P.E.
      • Chisolm G.M.
      ). In contrast, inhibition of PKC with staurosporine decreased oxidized LDL-induced DNA synthesis (
      • Chai Y.-C.
      • Howe P.H.
      • DiCorleto P.E.
      • Chisolm G.M.
      ). These findings suggest that PKC activation may contribute to the growth stimulation of both murine macrophages and vascular smooth muscle cells by oxidized LDL.
      The effects of oxidized LDL on other enzymes known to be involved in mitogenesis has also been investigated. Recently, Deigner et al. demonstrated MAP kinase activation in U937 cells stimulated with oxidized LDL, independent of PKC activation (
      • Deigner H.
      • Claus R.
      ). However, incubation of cells with native LDL induced an even greater increase in MAP kinase activity. Kusuhara and colleagues examined the effects of native or oxidized LDL on MAP kinase activity in smooth muscle cells, endothelial cells, and macrophages and found that both oxidized LDL and native LDL stimulated MAP kinase in a PKC-dependent manner (
      • Kusuhara M.
      • Chait A.
      • Cader A.
      • Berk B.C.
      ). However, in human monocyte-derived macrophages and in rat vascular smooth muscle cells the effect of oxidized LDL was greater than that of native LDL. Because native LDL does not induce growth of nontransformed macrophages or vascular smooth muscle cells (
      • Sakai M.
      • Miyazaki A.
      • Hakamata H.
      • Sasaki T.
      • Yui S.
      • Yamazaki M.
      • Shichiri M.
      • Horiuchi S.
      ,
      • Yui S.
      • Sasaki T.
      • Miyazaki A.
      • Horiuchi S.
      • Yamazaki M.
      ), it does not seem likely that MAP kinases are directly involved in the mitogenic effect of oxidized LDL. Phospholipase D activation has also been observed in vascular smooth muscle cells stimulated with oxidized LDL (
      • Natarajan V.
      • Scribner W.M.
      • Hart C.M.
      • Parthasarathy S.
      ). Phospholipase D activation results in the generation of phosphatidic acid and lysophosphatidic acid, both of which are known to be mitogenic (
      • van Corven E.J.
      • Groenink A.
      • Jalink K.
      • Eichholtz T.
      • Moolenaar W.H.
      ,
      • Tigyi G.
      • Dyer D.L.
      • Miledi R.
      ). However, at present there is no direct evidence linking phospholipase D activation to the mitogenic effect of oxidized LDL.
      Previous studies on growth stimulation by oxidized LDL suggested that the growth stimulation was mediated by a phospholipid component of oxidized LDL (
      • Sakai M.
      • Miyazaki A.
      • Hakamata H.
      • Sasaki T.
      • Yui S.
      • Yamazaki M.
      • Shichiri M.
      • Horiuchi S.
      ,
      • Heery J.M.
      • Kozak M.
      • Stafforini D.M.
      • Jones D.A.
      • Zimmerman G.A.
      • McIntyre T.M.
      • Prescott S.M.
      ). However, the possibility that the modified apoB of oxidized LDL may interact with membrane proteins and stimulate growth by a process analogous to integrin-mediated signaling (
      • Shatill S.J.
      • Ginsberg M.H.
      ) has not been excluded. Oxidized LDL binds to the scavenger receptor class A, type I/II, and it has been suggested that this receptor leads to tyrosine phosphorylation (
      • Miki S.
      • Tsukada S.
      • Nakamura Y.
      • Aimoto S.
      • Hojo H.
      • Sato B.
      • Yamamoto M.
      • Miki Y.
      ). However, acetyl LDL, which is an excellent ligand for the scavenger receptor class A, type I/II, does not stimulate macrophage growth, indicating that mere ligation of this receptor is not sufficient to induce growth. Oxidized LDL also binds to membrane proteins that do not interact well with acetyl LDL, including CD36, FcγRII, and macrosialin/CD68 (
      • Lougheed M.
      • Lum C.M.
      • Ling W.
      • Suzuki H.
      • Kodama T.
      • Steinbrecher U.
      ). The possibility that selective binding of oxidized LDL to these or other plasma membrane proteins may initiate the activation of mitogenic signal transduction cascades warrants further consideration.
      In conclusion, the data reported in this study provide evidence for a direct link between oxidized LDL-induced PI 3-kinase activation and macrophage growth. These findings not only increase our understanding of how oxidized LDL transmits its proliferative signal in macrophages but also provide insight into the signaling pathways that may be involved in some of the other biological functions of oxidized LDL. Further studies are required to identify the components of oxidized LDL that are responsible for growth stimulation and to define interactions with or effects mediated by other signaling pathways.

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