Ohara Y, Peterson T E, Sayegh H S, Subramanian R R, Wilcox J N, Harrison D G
Division of Cardiology, Emory University School of Medicine, Atlanta, GA 30322, USA.
Circulation. 1995 Aug 15;92(4):898-903. doi: 10.1161/01.cir.92.4.898.
We have shown that hypercholesterolemia increases vascular superoxide anion (O2-) production, which could be responsible for augmented inactivation of endothelium-derived vascular relaxing factor. We sought to determine whether this increased vascular O2- production is due to infiltration of macrophages into the intima and whether dietary treatment of hypercholesterolemia normalizes O2- production.
A specific and sensitive assay for O2- based on chemiluminescence of lucigenin was used; the amount of O2- produced by vascular ring segments was quantified based on known quantities of O2- produced by xanthine-xanthine oxidase standards. O2- production of aortic segments from normal rabbits (n = 9), cholesterol-fed rabbits (1% cholesterol diet for 1 month, n = 7), and rabbits fed a 1% cholesterol diet for 1 month followed by a normal diet for 1 month (regression rabbits, n = 5) was measured. At the end of these diets, serum cholesterol levels were 1.5 +/- 0.2, 26.0 +/- 3.9, and 1.8 +/- 0.5 mmol/L (58 +/- 6, 1000 +/- 150, and 71 +/- 19 mg/dL) in the normal, cholesterol-fed, and regression animals, respectively. Vessels from normal rabbits with endothelium produced 0.32 +/- 0.06 nmol O2-/mg dry wt per minute, whereas those without endothelium produced approximately twice as much O2- (0.66 +/- 0.12 nmol O2- mg dry wt per minute. Vessels with endothelium from cholesterol-fed rabbits produced 4.5-fold more O2- than vessels from normal animals. This increased production of O2- was normalized by endothelial removal. This increased production of O2- was not due to infiltration of macrophages in the intima, because there was no correlation between vascular O2- production and macrophage infiltration assessed by immunohistochemistry with use of a specific antibody against rabbit macrophage. O2- production by vessels from regression rabbits was similar to that observed in normal animals, and as in the normal rabbits, endothelial removal increased O2- production. Aortic rings from these animals also were studied in organ chambers. Dietary lowering of cholesterol dramatically improved vasodilator responses to acetylcholine and A23187 (P < .05 versus cholesterol-fed rabbits).
Dietary lowering of cholesterol not only improves endothelium-dependent vascular relaxation but also normalizes endothelial O2- production. Decreases of O2- production by dietary lowering of cholesterol not only may improve vasomotor control but also may improve other aspects of vascular integrity in atherosclerosis.
我们已经表明，高胆固醇血症会增加血管超氧阴离子（O₂⁻）的产生，这可能是内皮源性血管舒张因子失活增强的原因。我们试图确定这种血管O₂⁻产生的增加是否是由于巨噬细胞浸润到内膜，以及高胆固醇血症的饮食治疗是否能使O₂⁻产生恢复正常。
使用基于光泽精化学发光的O₂⁻特异性敏感测定法；根据黄嘌呤 - 黄嘌呤氧化酶标准产生的已知量的O₂⁻来量化血管环段产生的O₂⁻量。测量了正常兔（n = 9）、喂食胆固醇的兔（1%胆固醇饮食1个月；n = 7）以及先喂食1%胆固醇饮食1个月然后再喂食正常饮食1个月的兔（回归兔，n = 5）的主动脉段O₂⁻产生情况。在这些饮食结束时，正常组、喂食胆固醇组和回归组动物的血清胆固醇水平分别为1.5±0.2、26.0±3.9和1.8±0.5 mmol/L（58±6、1000±150和71±19 mg/dL）。有内皮正常兔的血管每分钟产生0.32±0.06 nmol O₂⁻/mg干重，而无内皮的血管产生的O₂⁻约为其两倍（0.66±0.12 nmol O₂⁻/mg干重每分钟）；喂食胆固醇兔有内皮的血管产生的O₂⁻比正常动物的血管多4.5倍。这种O₂⁻产生的增加通过去除内皮而恢复正常；这种O₂⁻产生的增加并非由于内膜巨噬细胞浸润，因为通过使用抗兔巨噬细胞特异性抗体的免疫组织化学评估，血管O₂⁻产生与巨噬细胞浸润之间没有相关性。回归兔血管的O₂⁻产生与正常动物相似，并且与正常兔一样，去除内皮会增加O₂⁻产生。还在器官浴槽中研究了这些动物的主动脉环。饮食降低胆固醇显著改善了对乙酰胆碱和A23187的血管舒张反应（与喂食胆固醇的兔相比，P < 0.05）。
饮食降低胆固醇不仅改善内皮依赖性血管舒张，还使内皮O₂⁻产生恢复正常。通过饮食降低胆固醇减少O₂⁻产生不仅可能改善血管舒缩控制，还可能改善动脉粥样硬化中血管完整性的其他方面。
