Endothelium dysfunction in LDL receptor knockout mice:: a role for H2O2

1 In this study, the role of endogenous H2O2 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 mum) and to the Ca2+ ionophore A23187 (0.001-3 mum) 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 mum) or L-NNA (100 mum) plus L-NAME (300 mum) plus haemoglobin (10 mum) markedly decreased, but did not abolish the relaxation to ACh in control mice. In the aortas from LDLR-/- mice treated with L-NNA (100 mum), ACh induced a contractile effect. Catalase (800 and 240OUml-') 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 mum) 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 H2O2 produced a concentration-dependent relaxation in endothelium-denuded aortic rings, which was not different between strains. 5 It is concluded that H2O2 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 H2O2 is the possible mechanism responsible for endothelial dysfunction in aortas of atherosclerosis-susceptible LDLR-/- mice.