Endothelium dysfunction in LDL receptor knockout mice: a role for H 2 O 2

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 −/− ). Aortic rings from LDLR −/− mice showed impaired endothelium‐dependent relaxation to acetylcholine (ACh; 0.001–100 μ M ) and to the Ca 2+ ionophore A23187 (0.001–3 μ 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. Pretreatment of vessels with L ‐NNA (100 μ M ) or L ‐NNA (100 μ M ) plus L ‐NAME (300 μ M ) plus haemoglobin (10 μ 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 μ 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 m M ), which inhibits catalase, abolished its effect on control mice. Treatment of vessels with L ‐NNA and catalase abolished vasorelaxation induced by ACh. Indomethacin (10 μ 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. Exogenous H 2 O 2 produced a concentration‐dependent relaxation in endothelium‐denuded aortic rings, which was not different between strains. 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.British Journal of Pharmacology (2003) 138 , 1215–1220. doi: 10.1038/sj.bjp.0705164