Endothelium-dependent vasorelaxation in the aorta of transgenic mice expressing human apolipoprotein(a) or lipoprotein(a)

Elevated plasma level of lipoprotein(a) (Lp(a)) is a well established risk factor for premature atherosclerosis and coronary artery disease. Recent st udies showed impaired endothelium-dependent vasodilatation in humans with e levated plasma Lp(a). However, these human studies could not determine whet her (1) elevated Lp(a) levels alone are the cause of endothelial dysfunctio n (these patients had multiple risk factors), and (2) native or oxidatively modified Lp(a) contributes to endothelial dysfunction (no measurements of native/oxidized Lp(a) ratio was reported in humans). In order to test wheth er apo(a) (an essential component of Lp(a) which is required for binding to endothelial cells) and native Lp(a) cause endothelial dysfunction, in the present study we tested endothelium-dependent vasorelaxation in aortic ring s isolated from control and transgenic male mice either expressing the huma n apo(a) gene (TgA) or both the human apo(a) and human apo B100 genes (TgL) . The TgA mice had plasma apo(a) levels of 8.8 +/- 1.2mg/dl (n=6) and the d ouble transgenic TgL mice had plasma Lp(a) levels of 15.3 +/- 1.4 mg/dl (n= 8). Isolated aortic rings with and without endothelium were mounted in orga n chambers and contracted with U46619 (10(-8)M) in the presence of ibuprofe n (10(-5)M). Acetylcholine caused concentration-dependent (10(-9) - 10(-3)M ) relaxation, which could be prevented by endothelium removal and by N-G-L- nitro-arginine (10(-4)M). Basal and acetylcholine-stimulated endothelium-de pendent relaxation and endothelium-independent relaxation to nitroglycerin (10(-6)M) were not significantly different in aortic rings isolated from co ntrol and TgA or TgL mice. Twenty-four hour incubation of aortic rings isol ated from control mice with recombinant human apo(a) or native Lp(a) (up to 300 mug/ml) caused no impairment of endothelium-dependent relaxations. In contrast, incubation with oxidized Lp(a) (50 mug/ml) or oxidized LDL (250 m ug/ml) caused significant suppression of acetylcholine-induced endothelium- dependent vasorelaxation. These results show for the first time that elevat ed plasma levels of apo(a) and Lp(a) do not cause endothelial dysfunction i n transgenic mice.