Kadowaki Daisuke, Anraku Makoto, Sakaya Moe, Hirata Sumio, Maruyama Toru, Otagiri Masaki
Department of Biopharmaceutics, Graduate School of Pharmaceutical Sciences, Kumamoto University, 5-1 Oe-honmachi, Chuo-ku, Kumamoto, 862-0973, Japan.
Center for Clinical Pharmaceutical Sciences, Kumamoto University, 5-1 Oe-honmachi, Chuo-ku, Kumamoto, Japan.
Clin Exp Nephrol. 2015 Dec;19(6):1007-14. doi: 10.1007/s10157-015-1111-5. Epub 2015 Apr 23.
The primary cause of death of hemodialysis (HD) patients is cardiovascular disease, and increased oxidative stress has been proposed to be involved in the disease pathogenesis. In this study, we examined the effect of olmesartan on oxidative stress induced by angiotensin II, lipopolysaccharide, indoxyl sulfate, advanced oxidation protein products (AOPP) or hydrogen peroxide (H2O2), which are known to be present at higher concentrations in the blood of HD patients, using human umbilical vein endothelial cells (HUVECs).
Oxidative stress was evaluated by measuring the mean fluorescence intensity of CM-H2DCFCA, an ROS-sensitive fluorescent dye, in HUVECs. HUVECs were incubated with each of the above compounds in the presence or absence of olmesartan. Moreover, these oxidant-stimulated cells were also treated with the reactive oxygen species (ROS) inhibitor N-acetyl-cysteine (NAC), NADPH oxidase inhibitor diphenylene iodonium (DPI) or PKC inhibitor calphostin C. In addition, we investigated the effects of olmesartan on cytotoxicity and vascular endothelial growth factor (VEGF) secretion, which is involved in vascular inflammation in HUVECs induced by AOPP or H2O2.
The treatment of these oxidant-stimulated cells with olmesartan resulted in a significant reduction in intracellular ROS production to an extent that was nearly equivalent to that of NAC, DPI or calphostin C. Furthermore, olmesartan reduced the cytotoxicity and VEGF secretion induced by AOPP or H2O2.
These results demonstrated that the antioxidant activity of olmesartan might contribute to both its vasculoprotective and anti-hypertensive effects.
血液透析（HD）患者的主要死因是心血管疾病，氧化应激增加被认为参与了该疾病的发病机制。在本研究中，我们使用人脐静脉内皮细胞（HUVECs），研究了奥美沙坦对血管紧张素II、脂多糖、硫酸吲哚酚、晚期氧化蛋白产物（AOPP）或过氧化氢（H2O2）诱导的氧化应激的影响，已知这些物质在HD患者血液中的浓度较高。
通过测量ROS敏感荧光染料CM-H2DCFCA在HUVECs中的平均荧光强度来评估氧化应激。HUVECs在有或没有奥美沙坦的情况下与上述每种化合物孵育。此外，这些氧化剂刺激的细胞还用活性氧（ROS）抑制剂N-乙酰半胱氨酸（NAC）、NADPH氧化酶抑制剂二苯基碘鎓（DPI）或PKC抑制剂钙泊三醇C处理。此外，我们研究了奥美沙坦对细胞毒性和血管内皮生长因子（VEGF）分泌的影响，VEGF分泌与AOPP或H2O2诱导的HUVECs血管炎症有关。
用奥美沙坦处理这些氧化剂刺激的细胞导致细胞内ROS产生显著减少，减少程度几乎与NAC、DPI或钙泊三醇C相当。此外，奥美沙坦降低了AOPP或H2O2诱导的细胞毒性和VEGF分泌。
这些结果表明，奥美沙坦的抗氧化活性可能有助于其血管保护和抗高血压作用。
