LOX-1 Augments OxLDL Uptake by LysoPC-stimulated Murine Macrophages but is Not Required for OxLDL Clearance from Plasma

Overview

Journal J Lipid Res

Publisher Elsevier

Specialty Biochemistry

Date 2009 Apr 11

PMID 19359704

Citations 33

Authors

David F Schaeffer

Maziar Riazy

Kuljit S Parhar

Johnny H Chen

Vincent Duronio

Tatsuya Sawamura

Urs P Steinbrecher

Affiliations

Soon will be listed here.

Abstract

Oxidized LDL (oxLDL) promotes lipid accumulation as well as growth and survival signaling in macrophages. OxLDL uptake is mainly due to scavenger receptors SR-AI/II and CD36. However, other scavenger receptors such as lectin-like oxLDL receptor-1 (LOX-1) may also play a role. We used mice with targeted inactivation of the LOX-1 gene to define the role of this receptor in the uptake of oxLDL and in activation of survival pathways. There was no difference in uptake or degradation of 125I-oxLDL in unstimulated macrophages from wild-type and LOX-1 knockout mice and no difference in the rate of clearance of oxLDL from plasma in vivo. However, when expression of LOX-1 was induced with lysophosphatidylcholine, oxLDL uptake and degradation increased 2-fold in wild-type macrophages but did not change in LOX-1 knockout macrophages. Macrophages lacking LOX-1 showed the same stimulation of PKB phosphorylation and enhancement of survival by oxLDL as wild-type cells. These data show that LOX-1 does not alter the uptake of oxLDL in unstimulated macrophages and is not essential for the pro-survival effect of oxLDL in these cells. However, LOX-1 expression is highly inducible by lysophosphatidylcholine and pro-inflammatory cytokines, and if that occurred in macrophages within atheromas, LOX-1 could substantially increase oxLDL uptake by lesion macrophages.

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References

Miller Y, Viriyakosol S, Binder C, Feramisco J, Kirkland T, Witztum J . Minimally modified LDL binds to CD14, induces macrophage spreading via TLR4/MD-2, and inhibits phagocytosis of apoptotic cells. J Biol Chem. 2002; 278(3):1561-8. DOI: 10.1074/jbc.M209634200. View

Nakagawa T, Yasuda T, Hoshikawa H, Shimizu M, Kakinuma T, Chen M . LOX-1 expressed in cultured rat chondrocytes mediates oxidized LDL-induced cell death-possible role of dephosphorylation of Akt. Biochem Biophys Res Commun. 2002; 299(1):91-7. DOI: 10.1016/s0006-291x(02)02597-4. View

Kataoka H, Kume N, Miyamoto S, Minami M, Moriwaki H, Murase T . Expression of lectinlike oxidized low-density lipoprotein receptor-1 in human atherosclerotic lesions. Circulation. 1999; 99(24):3110-7. DOI: 10.1161/01.cir.99.24.3110. View

Greaves D, Gordon S . Thematic review series: the immune system and atherogenesis. Recent insights into the biology of macrophage scavenger receptors. J Lipid Res. 2004; 46(1):11-20. DOI: 10.1194/jlr.R400011-JLR200. View

Kunjathoor V, Febbraio M, Podrez E, Moore K, Andersson L, Koehn S . Scavenger receptors class A-I/II and CD36 are the principal receptors responsible for the uptake of modified low density lipoprotein leading to lipid loading in macrophages. J Biol Chem. 2002; 277(51):49982-8. DOI: 10.1074/jbc.M209649200. View

Aoyama T, Fujiwara H, Masaki T, Sawamura T . Induction of lectin-like oxidized LDL receptor by oxidized LDL and lysophosphatidylcholine in cultured endothelial cells. J Mol Cell Cardiol. 2000; 31(12):2101-14. DOI: 10.1006/jmcc.1999.1041. View

Nagy L, Tontonoz P, Alvarez J, Chen H, Evans R . Oxidized LDL regulates macrophage gene expression through ligand activation of PPARgamma. Cell. 1998; 93(2):229-40. DOI: 10.1016/s0092-8674(00)81574-3. View

Steinbrecher U . Oxidation of human low density lipoprotein results in derivatization of lysine residues of apolipoprotein B by lipid peroxide decomposition products. J Biol Chem. 1987; 262(8):3603-8. View

Claus R, Fyrnys B, Deigner H, Wolf G . Oxidized low-density lipoprotein stimulates protein kinase C (PKC) and induces expression of PKC-isotypes via prostaglandin-H-synthase in P388D1 macrophage-like cells. Biochemistry. 1996; 35(15):4911-22. DOI: 10.1021/bi952036n. View

10.

Lougheed M, Steinbrecher U . Mechanism of uptake of copper-oxidized low density lipoprotein in macrophages is dependent on its extent of oxidation. J Biol Chem. 1996; 271(20):11798-805. DOI: 10.1074/jbc.271.20.11798. View

11.

Kataoka H, Kume N, Miyamoto S, Minami M, Morimoto M, Hayashida K . Oxidized LDL modulates Bax/Bcl-2 through the lectinlike Ox-LDL receptor-1 in vascular smooth muscle cells. Arterioscler Thromb Vasc Biol. 2001; 21(6):955-60. DOI: 10.1161/01.atv.21.6.955. View

12.

Imanishi T, Hano T, Sawamura T, Takarada S, Nishio I . Oxidized low density lipoprotein potentiation of Fas-induced apoptosis through lectin-like oxidized-low density lipoprotein receptor-1 in human umbilical vascular endothelial cells. Circ J. 2002; 66(11):1060-4. DOI: 10.1253/circj.66.1060. View

13.

Stanton L, WHITE R, Bryant C, Protter A, Endemann G . A macrophage Fc receptor for IgG is also a receptor for oxidized low density lipoprotein. J Biol Chem. 1992; 267(31):22446-51. View

14.

Moriwaki H, Kume N, Sawamura T, Aoyama T, Hoshikawa H, Ochi H . Ligand specificity of LOX-1, a novel endothelial receptor for oxidized low density lipoprotein. Arterioscler Thromb Vasc Biol. 1998; 18(10):1541-7. DOI: 10.1161/01.atv.18.10.1541. View

15.

Li D, Liu L, Chen H, Sawamura T, Ranganathan S, Mehta J . LOX-1 mediates oxidized low-density lipoprotein-induced expression of matrix metalloproteinases in human coronary artery endothelial cells. Circulation. 2003; 107(4):612-7. DOI: 10.1161/01.cir.0000047276.52039.fb. View

16.

Li D, Mehta J . Upregulation of endothelial receptor for oxidized LDL (LOX-1) by oxidized LDL and implications in apoptosis of human coronary artery endothelial cells: evidence from use of antisense LOX-1 mRNA and chemical inhibitors. Arterioscler Thromb Vasc Biol. 2000; 20(4):1116-22. DOI: 10.1161/01.atv.20.4.1116. View

17.

Lougheed M, Lum C, Ling W, Suzuki H, Kodama T, Steinbrecher U . High affinity saturable uptake of oxidized low density lipoprotein by macrophages from mice lacking the scavenger receptor class A type I/II. J Biol Chem. 1997; 272(20):12938-44. DOI: 10.1074/jbc.272.20.12938. View

18.

Bilheimer D, Eisenberg S, Levy R . The metabolism of very low density lipoprotein proteins. I. Preliminary in vitro and in vivo observations. Biochim Biophys Acta. 1972; 260(2):212-21. DOI: 10.1016/0005-2760(72)90034-3. View

19.

Tabas I . Consequences and therapeutic implications of macrophage apoptosis in atherosclerosis: the importance of lesion stage and phagocytic efficiency. Arterioscler Thromb Vasc Biol. 2005; 25(11):2255-64. DOI: 10.1161/01.ATV.0000184783.04864.9f. View

20.

Matsunaga T, Hokari S, Koyama I, Harada T, Komoda T . NF-kappa B activation in endothelial cells treated with oxidized high-density lipoprotein. Biochem Biophys Res Commun. 2003; 303(1):313-9. DOI: 10.1016/s0006-291x(03)00308-5. View