title: Deletion of LOX-1 reduces atherogenesis in LDLR knockout mice fed high cholesterol diet.
abstract: Atherosclerosis is associated with oxidative stress and inflammation, and upregulation of LOX-1, an endothelial receptor for oxidized LDL (oxLDL). Here, we describe generation of LOX-1 knockout (KO) mice in which binding of oxLDL to aortic endothelium was reduced and endothelium-dependent vasorelaxation preserved after treatment with oxLDL (P<0.01 versus wild-type mice). To address whether endothelial functional preservation might lead to reduction in atherogenesis, we crossed LOX-1 KO mice with LDLR KO mice and fed these mice 4% cholesterol/10% cocoa butter diet for 18 weeks. Atherosclerosis was found to cover 61+/-2% of aorta in the LDLR KO mice, but only 36+/-3% of aorta in the double KO mice. Luminal obstruction and intima thickness were significantly reduced in the double KO mice (versus LDLR KO mice). Expression of redox-sensitive NF-kappaB and the inflammatory marker CD68 in LDLR KO mice was increased (P<0.01 versus wild-type mice), but not in the double KO mice. On the other hand, antiinflammatory cytokine IL-10 expression and superoxide dismutase activity were low in the LDLR KO mice (P<0.01 versus wild-type mice), but not in the double KO mice. Endothelial nitric oxide synthase expression was also preserved in the double KO mice. The proinflammatory signal MAPK P38 was activated in the LDLR KO mice, and LOX-1 deletion reduced this signal. In conclusion, LOX-1 deletion sustains endothelial function leading to a reduction in atherogenesis in association with reduction in proinflammatory and prooxidant signals.
authors.affiliation: Cardiovascular Medicine, Gene Therapy Program, University of Arkansas for Medical Sciences, Little Rock, AR 72205. MehtaJL@uams.edu
authors.forename: Jawahar L
authors.initials: JL
authors.lastname: Mehta
authors.forename: Nobuhito
authors.initials: N
authors.lastname: Sanada
authors.forename: Chang Ping
authors.initials: CP
authors.lastname: Hu
authors.forename: Jiawei
authors.initials: J
authors.lastname: Chen
authors.forename: Abhijit
authors.initials: A
authors.lastname: Dandapat
authors.forename: Fumiaki
authors.initials: F
authors.lastname: Sugawara
authors.forename: Hiroo
authors.initials: H
authors.lastname: Satoh
authors.forename: Kazuhiko
authors.initials: K
authors.lastname: Inoue
authors.forename: Yosuke
authors.initials: Y
authors.lastname: Kawase
authors.forename: Kou-ichi
authors.initials: K
authors.lastname: Jishage
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Suzuki
authors.forename: Motohiro
authors.initials: M
authors.lastname: Takeya
authors.forename: Laura
authors.initials: L
authors.lastname: Schnackenberg
authors.forename: Richard
authors.initials: R
authors.lastname: Beger
authors.forename: Paul L
authors.initials: PL
authors.lastname: Hermonat
authors.forename: Maria
authors.initials: M
authors.lastname: Thomas
authors.forename: Tatsuya
authors.initials: T
authors.lastname: Sawamura
mesh_terms: D000818:Animals; D015703:Antigens, CD / Q000378:metabolism; D015214:Antigens, Differentiation, Myelomonocytic / Q000378:metabolism; D001011:Aorta / Q000378:metabolism / Q000473:pathology; D050197:Atherosclerosis / Q000235:genetics* / Q000473:pathology; D002478:Cells, Cultured; D002791:Cholesterol, Dietary; D003433:Crosses, Genetic; D004195:Disease Models, Animal; D018450:Disease Progression; D004730:Endothelium, Vascular / Q000378:metabolism / Q000473:pathology; D007249:Inflammation / Q000235:genetics / Q000473:pathology; D016753:Interleukin-10 / Q000378:metabolism; D008055:Lipids / Q000097:blood; D008077:Lipoproteins, LDL / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D016328:NF-kappa B / Q000378:metabolism; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism; D018384:Oxidative Stress / Q000235:genetics; D011973:Receptors, LDL / Q000235:genetics; D051127:Scavenger Receptors, Class E / Q000096:biosynthesis / Q000235:genetics*; D013482:Superoxide Dismutase / Q000378:metabolism; D014664:Vasodilation / Q000235:genetics; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism; D000097382:CD68 Molecule
chemical_list: D015703:Antigens, CD; D015214:Antigens, Differentiation, Myelomonocytic; D002791:Cholesterol, Dietary; D016753:Interleukin-10; D008055:Lipids; D008077:Lipoproteins, LDL; D016328:NF-kappa B; D052250:Nitric Oxide Synthase Type III; D011973:Receptors, LDL; D051127:Scavenger Receptors, Class E; D013482:Superoxide Dismutase; D048051:p38 Mitogen-Activated Protein Kinases; C067980:CD68 antigen, human; D000097382:CD68 Molecule; C495138:Olr1 protein, mouse; C099252:oxidized low density lipoprotein