Hein T W, Kuo L
Department of Medical Physiology, Microcirculation Research Institute, Texas A&M University Health Science Center, College Station 77843-1114, USA.
Circ Res. 1998 Aug 24;83(4):404-14. doi: 10.1161/01.res.83.4.404.
Oxidized LDLs (Ox-LDLs) inhibit endothelium-dependent dilation of isolated conduit arteries in a manner comparable to the impairment demonstrated in atherosclerotic vessels. However, it is not known whether the microvessels, which do not develop atherosclerotic lesions, are susceptible to Ox-LDL. Since endothelial release of NO plays an important role in vasodilation and since its dysfunction associated with atherosclerosis has been shown to extend into the coronary microcirculation, we hypothesized that Ox-LDLs impair endothelium-dependent vasodilation of coronary arterioles by reducing the synthesis and/or release of NO. To test this hypothesis, porcine subepicardial vessels (50 to 100 microm) were isolated, cannulated, and pressurized to 60 cm H2O without flow for in vitro study. Isolated vessels developed basal tone and dilated in a dose-dependent manner to the endothelium-dependent vasodilators serotonin, ATP, and ionomycin. These vasodilatory responses were inhibited by the NO synthase inhibitor NG-monomethyl-L-arginine and were subsequently reversed by extraluminal administration of the NO precursor L-arginine (3 mmol/L), suggesting the involvement of NO in these vasomotor responses. Intraluminal incubation of the vessels with native LDL (N-LDL) or Ox-LDL (1 mg protein/mL) significantly attenuated dilations to serotonin, ATP, and ionomycin. Ox-LDL produced more severe inhibition than did N-LDL, and the inhibitory effect was comparable to that of NG-monomethyl-L-arginine. The inhibitory effects of N-LDL and Ox-LDL were reversed by exogenous L-arginine (3 mmol/L) and were prevented by sodium dihydroxybenzene disulfonate (Tiron), a cell-permeable superoxide scavenger. In contrast, administration of the cell-impermeable superoxide scavenger superoxide dismutase prevented the inhibitory effect of N-LDL but not of Ox-LDL. In addition, the inhibitory effects of LDL were not restored by D-arginine or by removal of intraluminal LDL. Neither N-LDL nor Ox-LDL altered endothelium-independent vasodilation to sodium nitroprusside. These results indicate that coronary arterioles are susceptible to LDLs that specifically impair endothelium-dependent vasodilation by reducing NO synthesis. It is suggested that the initiation of superoxide anion production and the subsequent L-arginine deficiency may be responsible for the detrimental effect of LDL.
氧化型低密度脂蛋白（Ox-LDL）抑制离体传导动脉的内皮依赖性舒张，其方式与动脉粥样硬化血管中所表现出的损伤相似。然而，尚不清楚未发生动脉粥样硬化病变的微血管是否对Ox-LDL敏感。由于内皮释放一氧化氮（NO）在血管舒张中起重要作用，且已表明其与动脉粥样硬化相关的功能障碍会延伸至冠状动脉微循环，因此我们推测Ox-LDL通过减少NO的合成和/或释放来损害冠状动脉小动脉的内皮依赖性血管舒张。为了验证这一假设，分离猪的心外膜下血管（50至100微米），插管并在无血流的情况下加压至60厘米水柱进行体外研究。分离出的血管产生基础张力，并以剂量依赖性方式对内皮依赖性血管舒张剂5-羟色胺、三磷酸腺苷（ATP）和离子霉素舒张。这些血管舒张反应被一氧化氮合酶抑制剂N-甲基-L-精氨酸抑制，随后通过管腔外给予NO前体L-精氨酸（3毫摩尔/升）而逆转，这表明NO参与了这些血管舒缩反应。用天然低密度脂蛋白（N-LDL）或Ox-LDL（1毫克蛋白质/毫升）对血管进行管腔内孵育可显著减弱对5-羟色胺、ATP和离子霉素的舒张反应。Ox-LDL产生的抑制作用比N-LDL更严重，且抑制作用与N-甲基-L-精氨酸相当。N-LDL和Ox-LDL的抑制作用可被外源性L-精氨酸（3毫摩尔/升）逆转，并被细胞可渗透的超氧化物清除剂二羟基苯二磺酸钠（Tiron）阻止。相反，给予细胞不可渗透的超氧化物清除剂超氧化物歧化酶可阻止N-LDL的抑制作用，但不能阻止Ox-LDL的抑制作用。此外，D-精氨酸或去除管腔内的LDL均不能恢复LDL的抑制作用。N-LDL和Ox-LDL均未改变对硝普钠的非内皮依赖性血管舒张。这些结果表明冠状动脉小动脉对LDL敏感，LDL通过减少NO合成特异性损害内皮依赖性血管舒张。提示超氧阴离子生成的启动及随后的L-精氨酸缺乏可能是LDL产生有害作用的原因。
