title: Endothelium dysfunction in LDL receptor knockout mice: a role for H2O2.
abstract: 1. In this study, the role of endogenous H(2)O(2) as an endothelium-dependent relaxant factor was characterised in aortas from C57BL/6J and LDL receptor-deficient mice (LDLR(-/-)). 2. Aortic rings from LDLR(-/-) mice showed impaired endothelium-dependent relaxation to acetylcholine (ACh; 0.001-100 micro M) and to the Ca(2+) ionophore A23187 (0.001-3 micro M) compared with aortic rings from control mice. Endothelium-independent relaxation produced by the NO donor, 3-morpholino-sydnonimine (SIN-1) was not different between strains. 3. Pretreatment of vessels with L-NNA (100 micro M) or L-NNA (100 micro M) plus L-NAME (300 micro M) plus haemoglobin (10 micro M) markedly decreased, but did not abolish the relaxation to ACh in control mice. In the aortas from LDLR(-/-) mice treated with L-NNA (100 micro M), ACh induced a contractile effect. Catalase (800 and 2400 U ml(-1)) shifted to the right the endothelium-dependent relaxation to ACh in aortas from control but not from LDLR(-/-) mice. Aminotriazole (50 mM), which inhibits catalase, abolished its effect on control mice. Treatment of vessels with L-NNA and catalase abolished vasorelaxation induced by ACh. Indomethacin (10 micro M) did not modify the concentration-response curve to ACh. Superoxide dismutase (300 U ml(-1)) did not change ACh-induced relaxation in both strains. 4. Exogenous H(2)O(2) produced a concentration-dependent relaxation in endothelium-denuded aortic rings, which was not different between strains. 5. It is concluded that H(2)O(2) greatly contributes to relaxation to ACh in aorta from control mice. Endothelial-dependent relaxation to ACh is impaired in LDLR(-/-) mice. Reduced biosynthesis or increased inactivation of H(2)O(2) is the possible mechanism responsible for endothelial dysfunction in aortas of atherosclerosis-susceptible LDLR(-/-) mice.
authors.affiliation: Departamento de Fisiologia e Biofísica, ICB, Universidade Federal de Minas Gerais, Belo Horizonte, Brazil.
authors.forename: Luíza A
authors.initials: LA
authors.lastname: Rabelo
authors.forename: Steyner F
authors.initials: SF
authors.lastname: Cortes
authors.forename: Jacqueline I
authors.initials: JI
authors.lastname: Alvarez-Leite
authors.forename: Virgínia S
authors.initials: VS
authors.lastname: Lemos
mesh_terms: D000109:Acetylcholine / Q000378:metabolism / Q000494:pharmacology; D000640:Amitrole / Q000494:pharmacology; D000818:Animals; D001013:Aorta, Thoracic / Q000187:drug effects / Q000378:metabolism; D001161:Arteriosclerosis; D002374:Catalase / Q000494:pharmacology; D004727:Endothelium / Q000002:abnormalities* / Q000378:metabolism*; D045462:Endothelium-Dependent Relaxing Factors / Q000378:metabolism* / Q000494:pharmacology; D006861:Hydrogen Peroxide / Q000378:metabolism* / Q000494:pharmacology; D007213:Indomethacin / Q000494:pharmacology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout / Q000235:genetics* / Q000378:metabolism*; D008981:Molsidomine / Q000031:analogs & derivatives* / Q000494:pharmacology; D009126:Muscle Relaxation / Q000187:drug effects*; D009131:Muscle, Smooth, Vascular / Q000187:drug effects*; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D019335:Nitroarginine / Q000494:pharmacology; D010656:Phenylephrine; D011973:Receptors, LDL / Q000172:deficiency* / Q000235:genetics*; D013482:Superoxide Dismutase / Q000494:pharmacology
chemical_list: D045462:Endothelium-Dependent Relaxing Factors; D011973:Receptors, LDL; D010656:Phenylephrine; D019335:Nitroarginine; C002385:linsidomine; D006861:Hydrogen Peroxide; D008981:Molsidomine; D002374:Catalase; D013482:Superoxide Dismutase; D000109:Acetylcholine; D019331:NG-Nitroarginine Methyl Ester; D007213:Indomethacin; D000640:Amitrole