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首页> 外文学位 >Effect of homocysteine on bovine aortic endothelial cell function.
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Effect of homocysteine on bovine aortic endothelial cell function.

机译：同型半胱氨酸对牛主动脉内皮细胞功能的影响。

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摘要

Endothelial cell dysfunction is generally defined as impaired endothelial-dependent vasodilation (e.g. diminished NO production). Reactive oxygen species (ROS) such as superoxide anion (O2·−), nitric oxide (NO), H2O2 and peroxynitrite (ONOO− ) can be produced in vessels by certain pathological conditions to initiate or accentuate endothelial cell dysfunction. Hyperhomocysteinemia is an independent risk for cardiovascular diseases. About 5–7% of the general population has hyperhomocysteinemia. Hyperhomocysteinemia produces endothelial injury and dysfunction. Hyperhomocysteinemia also leads to increased ROS levels through auto-oxidation of homocysteine (HCY) and diminished anti-oxidative activities. Transport of L-arginine into endothelial cells appears to be critical for its availability to endothelial NOS (eNOS) for production of NO. When L-arginine availability to NOS is restricted, NOS acts principally upon O 2 to form O2·−. We hypothesize that hyperhomocysteinemia reduces cellular uptake of arginine, augments O 2·− production and causes endothelial dysfunction.; Aortic strips pretreated with HCY showed a substantial reduction in vasorelaxant response to acetylcholine as evidenced by a rightward shift (7 fold) and diminished maximal relaxation (80%) of the dose-response curve. These effects were substantially prevented by treatment with supplemental arginine. This indicates that HCY impairs endothelial-dependent relaxation by a mechanism involving arginine availability.; Treatment with HCY caused a biphasic effect on arginine transport. Acute treatment with HCY for 15 min and 2 hr did not alter arginine uptake in growth medium. After 6 hr incubation, uptake of arginine was increased in bovine aortic endothelial cells (BAECs) while arginine transport was reduced by 27% after 24 hr treatment in growth medium. However, in Hepes buffer HCY suppressed uptake of arginine after 15 min and 2 hr treatment. This suggests that arginine and proteins in growth medium had a protective effect.; Treatment with HCY also significantly reduced cellular levels of the CAT-1 arginine transporter protein (∼30%) after 24 hr treatment but not after 6 hr treatment, whereas levels of eNOS protein and activity were not altered. Moreover, HCY treatment caused membrane hyperpolarization after 6 hr and 24 hr treatment indicating that the drive for arginine uptake was maintained. Treatment with the antioxidants N-acetylcysteine and ascorbic acid reversed the HCY effect on arginine uptake, suggesting that oxidation of the transporter may contribute to the endothelial dysfunction. This concept was supported by observation of a significant increase in peroxynitrite formation (∼30%) after 24 hr treatment but not 6 hr treatment.; In summary, HCY-induced endothelial dysfunction appears to be due to enhanced oxidative stress, including formation of superoxide anion and peroxynitrite. Superoxide formation can occur from eNOS when the availability of arginine is limited. The action of HCY to reduce arginine uptake by reducing CAT-1 levels and possibly oxidizing the transporter may increase ROS formation and endothelial dysfunction.
机译：内皮细胞功能障碍通常被定义为内皮依赖性血管舒张受损（例如NO生成减少）。活性氧（ROS），例如超氧阴离子（O 2 ·-），一氧化氮（NO），H 2 O 2 和过氧亚硝酸盐（ONOO -）可能在某些病理条件下在血管中产生，从而引发或加剧内皮细胞功能障碍。高同型半胱氨酸血症是心血管疾病的独立风险。普通人群中约有5–7％患有高同型半胱氨酸血症。高同型半胱氨酸血症会引起内皮损伤和功能障碍。高同型半胱氨酸血症还通过同型半胱氨酸（HCY）的自氧化作用导致ROS水平升高，抗氧化活性降低。 L-精氨酸向内皮细胞的转运似乎对于其可被内皮型NOS（eNOS）产生NO至关重要。当L-精氨酸可用于NOS时，NOS主要作用于O 2 形成O 2 ·-。我们假设高同型半胱氨酸血症会降低精氨酸的细胞摄取，增加O 2 ·-的产生并引起内皮功能障碍。用HCY预处理的主动脉条显示出对乙酰胆碱的血管舒张反应的显着降低，这由剂量反应曲线的向右移动（7倍）和最大松弛（80％）减小所证明。通过补充精氨酸可以基本上防止这些影响。这表明HCY通过涉及精氨酸可用性的机制损害了内皮依赖性舒张。 HCY处理对精氨酸转运产生双相作用。用HCY进行15分钟和2小时的急性处理不会改变生长培养基中精氨酸的摄取。孵育6小时后，在生长培养基中处理24小时后，牛主动脉内皮细胞（BAEC）中精氨酸的摄取增加，而精氨酸转运减少27％。但是，在Hepes缓冲液中，HCY在15分钟和2小时处理后抑制了精氨酸的摄取。这表明生长培养基中的精氨酸和蛋白质具有保护作用。用HCY处理还可以显着降低24小时处理后而不是6小时处理后CAT-1精氨酸转运蛋白的细胞水平（约30％），而eNOS蛋白的水平和活性没有改变。而且，HCY处理在6小时和24小时处理后引起膜超极化，表明维持了精氨酸摄取的驱动力。用抗氧化剂N-乙酰半胱氨酸和抗坏血酸治疗可以逆转HCY对精氨酸摄取的影响，这表明转运蛋白的氧化可能导致内皮功能障碍。观察到24小时处理后过氧亚硝酸盐形成显着增加（约30％），但6小时处理未见明显增加，支持了这一概念。总之，HCY诱导的内皮功能障碍似乎是由于氧化应激增强，包括形成超氧阴离子和过氧亚硝酸盐。当精氨酸的可用性受到限制时，eNOS可能会形成超氧化物。 HCY通过降低CAT-1水平并可能氧化转运蛋白来减少精氨酸摄取的作用可能会增加ROS的形成和内皮功能障碍。

著录项

  • 作者

    Jin, Liming.;

  • 作者单位

    Medical College of Georgia.;

  • 授予单位 Medical College of Georgia.;
  • 学科 Health Sciences Pharmacology.
  • 学位 Ph.D.
  • 年度 2001
  • 页码 87 p.
  • 总页数 87
  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类 药理学;
  • 关键词

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