Mechanism of Endothelial Dysfunction in Apolipoprotein E–Deficient Mice

Abstract

—Endothelium-dependent relaxations mediated by NO are impaired in a mouse model of human atherosclerosis. Our objective was to characterize the mechanisms underlying endothelial dysfunction in aortas of apolipoprotein E (apoE)-deficient mice, treated for 26 to 29 weeks with a lipid-rich Western-type diet. Aortic rings from apoE-deficient mice showed impaired endothelium-dependent relaxations to acetylcholine (10 ^{− 9} to 10 ^{− 5} mol/L) and Ca ²⁺ ionophore (10 ^{− 9} to 10 ^{− 6} mol/L) and endothelium-independent relaxations to diethylammonium ( Z )-1-( N , N -diethylamino)diazen-1-ium-1,2-diolate (DEA-NONOate, 10 ^{− 10} to 10 ^{− 5} mol/L) compared with aortic rings from C57BL/6J mice ( P 2 ⁻ ) production was demonstrated throughout the aortic wall but mainly in smooth muscle cells of apoE-deficient mice. CuZn–superoxide dismutase (SOD) and Mn-SOD protein expressions were unaltered in the aorta exposed to hypercholesterolemia. A cell-permeable SOD mimetic, Mn(III) tetra(4-benzoic acid) porphyrin chloride (10 ^{− 5} mol/L), reduced O ₂ ⁻ production and partially normalized relaxations to acetylcholine and DEA-NONOate in apoE-deficient mice ( P 14 C] l -Citrulline assay showed a decrease of Ca ²⁺ -dependent NOS activity in aortas from apoE-deficient mice compared with C57BL/6J mice ( P P 2 ⁻ and reduced endothelial NO synthase enzyme activity. Thus, chemical inactivation of NO with O ₂ ⁻ and reduced biosynthesis of NO are key mechanisms responsible for endothelial dysfunction in aortas of atherosclerotic apoE-deficient mice.