title: Oxidized low density lipoprotein (LDL) affects hyaluronan synthesis in human aortic smooth muscle cells.
abstract: Thickening of the vessel in response to high low density lipoprotein(s) (LDL) levels is a hallmark of atherosclerosis, characterized by increased hyaluronan (HA) deposition in the neointima. Human native LDL trapped within the arterial wall undergoes modifications such as oxidation (oxLDL). The aim of our study is to elucidate the link between internalization of oxLDL and HA production in vitro, using human aortic smooth muscle cells. LDL were used at an effective protein concentration of 20-50 μg/ml, which allowed 80% cell viability. HA content in the medium of untreated cells was 28.9 ± 3.7 nmol HA-disaccharide/cell and increased after oxLDL treatment to 53.9 ± 5.6. OxLDL treatments doubled the transcripts of HA synthase HAS2 and HAS3. Accumulated HA stimulated migration of aortic smooth muscle cells and monocyte adhesiveness to extracellular matrix. The effects induced by oxLDL were inhibited by blocking LOX-1 scavenger receptor with a specific antibody (10 μg/ml). The cholesterol moiety of LDL has an important role in HA accumulation because cholesterol-free oxLDL failed to induce HA synthesis. Nevertheless, cholesterol-free oxLDL and unmodified cholesterol (20 μg/ml) induce only HAS3 transcription, whereas 22,oxysterol affects both HAS2 and HAS3. Moreover, HA deposition was associated with higher expression of endoplasmic reticulum stress markers (CHOP and GRP78). Our data suggest that HA synthesis can be induced in response to specific oxidized sterol-related species delivered through oxLDL.
authors: From the Dipartimento di Scienze Chirurgiche e Morfologiche, Università degli Studi dell'Insubria, via J. H. Dunant 5, 21100 Varese, Italy.
authors: Manuela
authors: M
authors: Viola
authors: Barbara
authors: B
authors: Bartolini
authors: Davide
authors: D
authors: Vigetti
authors: Evgenia
authors: E
authors: Karousou
authors: Paola
authors: P
authors: Moretto
authors: Sara
authors: S
authors: Deleonibus
authors: Tatsuya
authors: T
authors: Sawamura
authors: Thomas N
authors: TN
authors: Wight
authors: Vincent C
authors: VC
authors: Hascall
authors: Giancarlo
authors: G
authors: De Luca
authors: Alberto
authors: A
authors: Passi
mesh_terms: D000906:Antibodies / Q000276:immunology / Q000494:pharmacology; D001011:Aorta / Q000166:cytology; D002448:Cell Adhesion / Q000187:drug effects; D002465:Cell Movement / Q000187:drug effects*; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D000091342:Endoplasmic Reticulum Chaperone BiP; D005109:Extracellular Matrix / Q000378:metabolism; D015870:Gene Expression / Q000187:drug effects; D014453:Glucuronosyltransferase / Q000235:genetics; D006801:Humans; D000076002:Hyaluronan Synthases; D006820:Hyaluronic Acid / Q000096:biosynthesis*; D008077:Lipoproteins, LDL / Q000378:metabolism / Q000494:pharmacology*; D009000:Monocytes / Q000187:drug effects / Q000378:metabolism; D032389:Myocytes, Smooth Muscle / Q000187:drug effects* / Q000378:metabolism; D010084:Oxidation-Reduction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D051127:Scavenger Receptors, Class E / Q000037:antagonists & inhibitors / Q000276:immunology / Q000378:metabolism; D020298:U937 Cells
chemical_list: D000906:Antibodies; D000091342:Endoplasmic Reticulum Chaperone BiP; C000717247:HSPA5 protein, human; D008077:Lipoproteins, LDL; C495137:OLR1 protein, human; D051127:Scavenger Receptors, Class E; C099252:oxidized low density lipoprotein; D006820:Hyaluronic Acid; D014453:Glucuronosyltransferase; C101754:HAS2 protein, human; C105458:HAS3 protein, human; D000076002:Hyaluronan Synthases
keywords: Atherosclerosis; Cholesterol; Glycosaminoglycan; Scavenger Receptor; Vascular Smooth Muscle Cells
references: Nat Rev Mol Cell Biol. 2008 Feb;9(2):125-38
references: 18216769
references: Glycobiology. 2009 May;19(5):537-46
references: 19240269
references: J Biol Chem. 2009 Oct 30;284(44):30684-94
references: 19737932
references: Cell. 2006 Jan 13;124(1):35-46
references: 16413480
references: Arterioscler Thromb Vasc Biol. 2007 May;27(5):1159-65
references: 17303781
references: Nat Rev Mol Cell Biol. 2012 Mar 14;13(4):213-24
references: 22414897
references: Arterioscler Thromb Vasc Biol. 2011 Jun;31(6):1309-16
references: 21441139
references: Arterioscler Thromb Vasc Biol. 2000 Jun;20(6):1572-9
references: 10845874
references: J Biol Chem. 2011 Oct 7;286(40):34497-503
references: 21768115
references: Arterioscler Thromb Vasc Biol. 2004 Dec;24(12):2211-8
references: 15472124
references: Arterioscler Thromb Vasc Biol. 2003 May 1;23(5):712-9
references: 12615688
references: Ann N Y Acad Sci. 2012 Apr;1254:18-32
references: 22548566
references: Arterioscler Thromb Vasc Biol. 1998 Oct;18(10):1541-7
references: 9763524
references: Antioxid Redox Signal. 2006 May-Jun;8(5-6):691-728
references: 16771662
references: Circulation. 1999 Jun 22;99(24):3110-7
references: 10377073
references: Proc Natl Acad Sci U S A. 2003 Nov 11;100(23):13531-6
references: 14581613
references: J Biol Chem. 2003 Nov 21;278(47):47223-31
references: 12954638
references: Arterioscler Thromb Vasc Biol. 1999 Apr;19(4):1004-13
references: 10195929
references: J Lipid Res. 1997 Nov;38(11):2264-72
references: 9392424
references: FASEB J. 2011 Feb;25(2):576-89
references: 20966213
references: Circulation. 2010 Nov 30;122(22):2313-22
references: 21098434
references: Am J Pathol. 1985 Nov;121(2):200-11
references: 3840653
references: J Biol Chem. 2010 Jul 30;285(31):23647-54
references: 20507985
references: Physiol Rev. 2011 Jan;91(1):221-64
references: 21248167
references: Arterioscler Thromb Vasc Biol. 2008 May;28(5):812-9
references: 18276911
references: FASEB J. 2006 Jun;20(8):1118-30
references: 16770011
references: Free Radic Biol Med. 2012 Jan 1;52(1):19-34
references: 22037514
references: Trends Cell Biol. 2010 Nov;20(11):680-7
references: 20843692
references: Physiol Rev. 2000 Jan;80(1):361-554
references: 10617772
references: Atherosclerosis. 1996 Dec 20;127(2):195-203
references: 9125309
references: Nature. 2002 Jun 13;417(6890):750-4
references: 12066187
references: Expert Rev Mol Med. 2011 Feb 03;13:e4
references: 21288373
references: Nat Cell Biol. 2003 Sep;5(9):781-92
references: 12907943
references: Circ Res. 2005 Mar 18;96(5):583-91
references: 15705963
references: Exp Cell Res. 2012 Oct 1;318(16):2128-42
references: 22728266
references: J Biol Chem. 2010 Jul 23;285(30):22901-10
references: 20501660
references: Proc Natl Acad Sci U S A. 2010 Jul 13;107(28):12564-9
references: 20538976
references: Cell Metab. 2011 Apr 6;13(4):367-375
references: 21459322
references: Arterioscler Thromb Vasc Biol. 2006 Mar;26(3):494-500
references: 16357313
references: Arterioscler Thromb Vasc Biol. 2002 Oct 1;22(10):1642-8
references: 12377743
references: Circulation. 1996 Mar 15;93(6):1141-7
references: 8653834
references: Cardiovasc Drugs Ther. 2011 Oct;25(5):419-29
references: 21947818
references: J Biol Chem. 2008 Dec 26;283(52):36195-204
references: 18948257
references: Electrophoresis. 2004 Sep;25(17):2919-25
references: 15349930
references: Biochim Biophys Acta. 2000 Nov 15;1488(3):189-210
references: 11082530
references: Antioxid Redox Signal. 2011 Oct 15;15(8):2301-33
references: 21338316
references: J Biol Chem. 2008 Feb 15;283(7):4448-58
references: 18077444
references: J Gen Physiol. 2000 Apr;115(4):405-16
references: 10736308
references: J Biol Chem. 2002 Feb 15;277(7):4593-6
references: 11717318
references: Atherosclerosis. 2009 Nov;207(1):38-44
references: 19426978
references: Curr Atheroscler Rep. 2012 Jan 29;:
references: 22286193
references: Clin Chim Acta. 2010 Dec 14;411(23-24):1875-82
references: 20816951
references: J Biol Chem. 2010 Aug 6;285(32):24639-45
references: 20522558
references: J Biol Chem. 2011 Mar 11;286(10):7917-7924
references: 21228273
references: FEBS Lett. 1997 Feb 17;403(2):154-8
references: 9042957
references: J Biol Chem. 2012 Apr 20;287(17):14122-35
references: 22351750
references: J Biol Chem. 2012 Oct 12;287(42):35544-35555
references: 22887999
references: Physiol Rev. 2004 Oct;84(4):1381-478
references: 15383655