Effect of native and oxidized low-density lipoprotein on endothelial nitric oxide and superoxide production : key role of L-arginine availability.
Effect of native and oxidized low-density lipoprotein on endothelial nitric oxide and superoxide production : key role of L-arginine availability.
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DOI：
10.1161/01.cir.101.11.1261
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发表时间：
2000-03
期刊：
影响因子：
37.8
通讯作者：
L. Vergnani;S. Hatrík;F. Ricci;A. Passaro;N. Manzoli;G. Zuliani;V. Brovkovych;R. Fellin;T. Malinski
中科院分区：
文献类型：
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作者：
L. Vergnani;S. Hatrík;F. Ricci;A. Passaro;N. Manzoli;G. Zuliani;V. Brovkovych;R. Fellin;T. Malinski
背景天然和氧化低密度脂蛋白(n-LDL和ox-LDL)参与动脉粥样硬化形成过程，并通过与一氧化氮(NO)相互作用影响内皮依赖性血管张力。方法与结果在本研究中，我们使用一种卟啉微传感器，直接评估了增加脂蛋白浓度对内皮细胞NO和超氧化物(O(2)(-))产生的影响。我们用L-精氨酸、L-N-精氨酸甲酯(L-NAME)和超氧化物歧化酶处理细胞，研究了脂蛋白对L-精氨酸-NO途径的影响。将牛主动脉内皮细胞暴露于n-低密度脂蛋白(从0到240 mg胆固醇/dL)和氧化低密度脂蛋白(从0到140 mg胆固醇/dL)浓度增加1小时。当n-低密度脂蛋白浓度为80 mg胆固醇/dL时，受刺激的钙离子载体NO浓度降至对照组的29%，而当氧化型低密度脂蛋白浓度为20 mg胆固醇/dL时，刺激后的NO浓度降至对照组的15%。L精氨酸可部分中和n-低密度脂蛋白和氧化低密度脂蛋白对NO生成的抑制作用。超氧化物歧化酶处理不改变NO的产生，而L的名字在所有低密度脂蛋白浓度下钝化NO的产生。在低n-低密度脂蛋白和极低氧化低密度脂蛋白浓度下，O(2)(-)的产生增加；这一作用被L精氨酸逆转。结论这些结果证实了n-低密度脂蛋白和氧化低密度脂蛋白对NO生成的抑制作用，提示脂蛋白可能导致L-精氨酸摄取减少。L-精氨酸底物的局部耗竭可能导致NO合酶的紊乱，导致NO合酶的另一种底物氧产生过量的O(2)(-)。
BACKGROUND Native and oxidized LDLs (n-LDL and ox-LDL) are involved in the atherogenic process and affect endothelium-dependent vascular tone through their interaction with nitric oxide (NO). METHODS AND RESULTS In this study we evaluated directly, by using a porphyrinic microsensor, the effect of increasing lipoprotein concentrations on endothelial NO and superoxide (O(2)(-)) production. We investigated where lipoproteins may affect the L-arginine-NO pathway by pretreating cells with L-arginine, L-N-arginine methyl ester (L-NAME), and superoxide dismutase. Bovine aortic endothelial cells were exposed for 1 hour to increasing concentrations of n-LDL (from 0 to 240 mg cholesterol/dL) and ox-LDL (from 0 to 140 mg cholesterol/dL). A stimulated (calcium ionophore) NO concentration decreased to 29% of the control at n-LDL concentration of 80 mg cholesterol/dL and to 15% of the control at 20 mg cholesterol/dL of ox-LDL. L-Arginine partially neutralized the inhibitory effect of n-LDL and ox-LDL on the NO generation. Superoxide dismutase pretreatment did not modify NO production, whereas L-NAME blunted NO generation at all LDL concentrations. O(2)(-) production was increased at low n-LDL and very low ox-LDL concentrations; this was reversed by L-arginine. CONCLUSIONS These findings confirm the inhibitory role of n-LDL and ox-LDL on NO generation and suggest that lipoproteins may induce a decreased uptake of L-arginine. The local depletion of the L-arginine substrate may derange the NO synthase, leading to overproduction of O(2)(-) from oxygen, the other substrate of NO synthase.