title: Known players, new interplay in atherogenesis: Chronic shear stress and carbamylated-LDL induce and modulate expression of atherogenic LR11 in human coronary artery endothelium.
abstract: In this study we examined whether low-density lipoprotein (LDL) receptor family members represent a link between blood flow characteristics and modified low-density lipoproteins involved in endothelial injury, a pivotal factor in atherogenesis. We demonstrated the expression of pro-atherogenic LDL receptor relative (LR11) for the first time in human coronary artery endothelial cells (HCAEC) in vitro and in vivo. Next, LR11 expression and regulation were explored in HCAEC cultured conventionally or on the inner surface of hollow fiber capillaries under exposure to shear stress for 10 days in the presence or absence of LDL. There was no LR11 expression under static conditions. When exposed to chronic low shear stress (2.5 dynes/cm²) transmembrane and soluble endothelial-LR11 were detected in high levels irrespective of the type of LDL added (carbamylated or native). In contrast, chronic high shear stress (25 dynes/cm²) inhibited the LR11-inducing effect of LDL such that transmembrane and soluble LR11 expression became non-detectable with native LDL. Carbamylated LDL significantly counteracted this atheroprotective effect of high shear stress as shown by lower, yet sustained expression of soluble and transmembrane LR11. Oxidised LDL showed similar effects compared to carbamylated LDL but caused significantly lower LR11 expression under chronic high shear stress. Medium from HCAEC under LR11-inducing conditions enhanced vascular smooth muscle cell migration, which was abrogated by the anti-LR11 antibody. Expression of LR11 depended entirely on p38MAPK phosphorylation. We conclude that coronary endothelial LR11 expression modulated by LDL and chronic shear stress contributes to atherogenesis. LR11 and p38MAPK are potential targets for prevention of atherosclerosis.
authors.forename: Tarek M
authors.initials: TM
authors.lastname: Bajari
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Winnicki
authors.forename: Eva-Theres
authors.initials: ET
authors.lastname: Gensberger
authors.forename: Susanna I
authors.initials: SI
authors.lastname: Scharrer
authors.forename: Heinz
authors.initials: H
authors.lastname: Regele
authors.forename: Klaus
authors.initials: K
authors.lastname: Aumayr
authors.forename: Chantal
authors.initials: C
authors.lastname: Kopecky
authors.forename: Bernhard M
authors.initials: BM
authors.lastname: Gmeiner
authors.forename: Marcela
authors.initials: M
authors.lastname: Hermann
authors.forename: Robert
authors.initials: R
authors.lastname: Zeillinger
authors.affiliation: Gürkan Sengölge, MD, Department of Medicine III, Division of Nephrology and Dialysis, Medical University of Vienna, Waehringer Guertel 18-20, A-1090, Vienna, Austria, Tel.: +43 1 40400 4390, Fax: +43 1 40400 4392, E-mail: guerkan.sengoelge@meduniwien.ac.at.
authors.forename: Gürkan
authors.initials: G
authors.lastname: Sengölge
mesh_terms: D050197:Atherosclerosis / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D002465:Cell Movement; D049109:Cell Proliferation; D002478:Cells, Cultured; D003324:Coronary Artery Disease / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D003331:Coronary Vessels / Q000378:metabolism* / Q000473:pathology; D017077:Culture Media, Conditioned / Q000378:metabolism; D042783:Endothelial Cells / Q000378:metabolism* / Q000473:pathology; D004789:Enzyme Activation; D006801:Humans; D026502:LDL-Receptor Related Proteins / Q000378:metabolism*; D008077:Lipoproteins, LDL / Q000378:metabolism*; D040542:Mechanotransduction, Cellular; D026901:Membrane Transport Proteins / Q000378:metabolism*; D009131:Muscle, Smooth, Vascular / Q000378:metabolism; D032389:Myocytes, Smooth Muscle / Q000378:metabolism; D010766:Phosphorylation; D013314:Stress, Mechanical; D013997:Time Factors; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
chemical_list: D017077:Culture Media, Conditioned; D026502:LDL-Receptor Related Proteins; D008077:Lipoproteins, LDL; D026901:Membrane Transport Proteins; C102582:SORL1 protein, human; C039916:carbamyl-LDL; C099252:oxidized low density lipoprotein; D048051:p38 Mitogen-Activated Protein Kinases
keywords: Atherosclerosis; endothelium; modified lipoproteins; shear stress; smooth muscle cell