Barton M, Haudenschild C C, d'Uscio L V, Shaw S, Münter K, Lüscher T F
Cardiology, University Hospital Zürich and Cardiovascular Research Laboratory, Institute of Physiology, University of Zürich, CH-8091 Zurich, Switzerland.
Proc Natl Acad Sci U S A. 1998 Nov 24;95(24):14367-72. doi: 10.1073/pnas.95.24.14367.
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 micromol/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 micromol/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.
本研究调查了强效血管收缩剂内皮素 -1（ET-1）（其也刺激细胞增殖）是否会导致内皮功能障碍和动脉粥样硬化。将载脂蛋白E（apoE）缺陷小鼠和C57BL/6对照小鼠用西式饮食处理30周，以加速动脉粥样硬化的发展，处理过程中一组给予或不给予ETA受体拮抗剂LU135252（50毫克/千克/天）。测定收缩压、血浆脂质谱和血浆硝酸盐水平。评估主动脉中一氧化氮（NO）介导的内皮依赖性舒张、动脉粥样硬化形成、ET受体结合能力和血管ET-1蛋白含量。在30周内，apoE缺陷小鼠而非C57BL/6小鼠出现了严重的动脉粥样硬化。与C57BL/6小鼠相比，apoE缺陷小鼠主动脉ET-1蛋白含量增加（P < 0.0001），ETA受体结合能力增强。相反，NO介导的对乙酰胆碱的内皮依赖性舒张作用降低（56±3% 对 99±2%，P < 0.0001），血浆硝酸盐水平也降低（57.9±4微摩尔/升对93±10微摩尔/升，P < 0.01）。用ETA受体拮抗剂LU135252处理30周对apoE缺陷小鼠的脂质谱或收缩压没有影响，但增加了NO介导的内皮依赖性舒张（从56±3%增加到93±2%，与未处理组相比P < 0.0001）以及循环硝酸盐水平（从57.9±4微摩尔/升增加到80±8.3微摩尔/升，P < 0.05）。长期阻断ETA受体可降低组织中升高的ET-1水平，使其与C57BL/6小鼠中的水平相当，并抑制主动脉中31%的动脉粥样硬化形成，且不影响斑块形态或ET受体结合能力。因此，在人类动脉粥样硬化小鼠模型中，长期阻断ETA受体可使NO介导的内皮功能障碍恢复正常，并减少动脉粥样硬化形成，且独立于血浆胆固醇和血压。ETA受体阻断可能对动脉粥样硬化患者具有治疗潜力。
