Endothelin ETA receptor blockade restores NO-mediated endothelial function and inhibits atherosclerosis in apolipoprotein E-deficient mice
Endothelin ETA receptor blockade restores NO-mediated endothelial function and inhibits atherosclerosis in apolipoprotein E-deficient mice
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DOI：
10.1073/pnas.95.24.14367
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发表时间：
1998-11-24
影响因子：
11.1
通讯作者：
Lüscher, TF
中科院分区：
文献类型：
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作者：
Barton, M;Haudenschild, CC;Lüscher, TF
本研究探讨内皮素-1（ET-1），一种有效的血管收缩剂，也刺激细胞增殖，是否有助于内皮功能障碍和动脉粥样硬化，载脂蛋白E（apoE）缺陷小鼠和C57 BL/6对照小鼠用西式饮食处理，以加速动脉粥样硬化，有或没有ETA受体拮抗剂LU 135252（50 mg/kg/d）连续给药30 wk，测定血压、血脂和硝酸盐水平。在主动脉中，评估NO介导的内皮依赖性舒张、粥样硬化形成、ET受体结合能力和血管ET-1蛋白含量。ApoE基因敲除的C57 BL/6小鼠在30周内出现严重的动脉粥样硬化，与C57 BL/6小鼠相比，主动脉ET-1蛋白含量（P < 0.0001）和ETA受体结合量（P < 0.0001）增加。相反，NO介导的内皮依赖性舒张对乙酰胆碱（56 +/- 3 vs. 99 +/-2%，P < 0.0001）和血浆硝酸盐降低（57.9 +/- 4 vs，93 +/- 10 μ mol/L，P < 0.01），用ETA受体拮抗剂LU 135252治疗30周对apoE缺陷小鼠的血脂谱或收缩压没有影响，但增加NO介导的内皮依赖性舒张（从56 +/- 3到93 +/-2%，P < 0.0001，与未治疗组相比）以及循环硝酸盐水平（从57.9 ± 4 μ mol/L到80 ± 8.3 μ mol/L，P < 0.05），慢性ETA受体阻断降低了升高的组织ET-1水平，与C57 BL/6小鼠中发现的水平相当，并抑制了31%的主动脉粥样硬化，而不影响斑块形态或ET受体结合能力。因此，在人类动脉粥样硬化的小鼠模型中，慢性ETA受体阻断剂使NO介导的内皮功能障碍正常化，并减少不依赖于血浆胆固醇和血压的动脉粥样硬化形成。ETA受体阻断剂可能对动脉粥样硬化患者具有治疗潜力。
This study investigated whether endothelin-1 (ET-1), a potent vasoconstrictor, which also stimulates cell proliferation, contributes to endothelial dysfunction and atherosclerosis, Apolipoprotein E (apoE)-deficient mice and C57BL/6 control mice were treated with a Western-type diet to accelerate atherosclerosis with or without ETA receptor antagonist LU135252 (50 mg/kg/d) for 30 wk, Systolic blood pressure, plasma lipid profile, and plasma nitrate levels were determined. In the aorta, NO-mediated endothelium-dependent relaxation, atheroma formation, ET receptor-binding capacity, and vascular ET-1 protein content were assessed. In apoE-deficient but not C57BL/6 mice, severe atherosclerosis developed within 30 wk, Aortic ET-1 protein content (P < 0.0001) and binding capacity for ETA receptors was increased as compared with C57BL/6 mice. In contrast, NO-mediated, endothelium-dependent relaxation to acetylcholine (56 +/- 3 vs. 99 +/- 2%, P < 0.0001) and plasma nitrate were reduced (57.9 +/- 4 vs, 93 +/- 10 mu mol/liter, P < 0.01), Treatment with the ETA receptor antagonist LU135252 for 30 wk had no effect on the lipid profile or systolic blood pressure in apoE-deficient mice, but increased NO-mediated endothelium-dependent relaxation (from 56 +/- 3 to 93 +/- 2%, P < 0.0001 vs, untreated) as well as circulating nitrate levels (from 57.9 +/- 4 to 80 +/- 8.3 mu mol/liter, P < 0.05), Chronic ETA receptor blockade reduced elevated tissue ET-1 levels comparable with those found in C57BL/6 mice and inhibited atherosclerosis in the aorta by 31% without affecting plaque morphology or ET receptor-binding capacity. Thus, chronic ETA receptor blockade normalizes NO-mediated endothelial dysfunction and reduces atheroma formation independent of plasma cholesterol and blood pressure in a mouse model of human atherosclerosis. ETA receptor blockade may have therapeutic potential in patients with atherosclerosis.