Receptor-independent intracellular radical scavenging activity of an angiotensin II receptor blocker
Receptor-independent intracellular radical scavenging activity of an angiotensin II receptor blocker
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DOI：
10.1097/hjh.0b013e328165d159
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发表时间：
2007-08
影响因子：
4.9
通讯作者：
Jing Shao;M. Nangaku;R. Inagi;Hideki Kato;T. Miyata;T. Matsusaka;E. Noiri;T. Fujita
中科院分区：
文献类型：
--
作者：
Jing Shao;M. Nangaku;R. Inagi;Hideki Kato;T. Miyata;T. Matsusaka;E. Noiri;T. Fujita
目的血管紧张素II（Angiotensin II，Ang II）在氧化应激的诱导以及心血管和肾脏疾病的发病机制中起重要作用，而血管紧张素II受体1（Angiotensin II receptor 1，ARB）阻滞剂（angiotensin II receptor 1 blockers，ARB）的作用机制是多方面的。我们使用血管紧张素II受体1敲除或野生型小鼠的原代培养系膜细胞和高度亲脂性ARB替米沙坦研究了ARB的受体非依赖性保护作用。方法和结果细胞内活性氧估计使用荧光探针，CM-H2 DCFDA。通过将细胞单独暴露于过氧化氢或在替米沙坦处理后产生非血管紧张素II诱导的活性氧。流式细胞术分析表明，血管紧张素II诱导的氧化剂产量增加，在野生型细胞中的剂量依赖性的方式，但不是在敲除细胞。与此相反，过氧化氢诱导的氧化应激在野生型和敲除细胞。有趣的是，替米沙坦减弱了两种细胞中过氧化氢诱导的氧化应激，表明其通过受体非依赖性抗氧化作用发挥作用。通过高效液相色谱分析证实了替米沙坦的细胞内浓度。替米沙坦还以受体非依赖性和受体依赖性方式减弱了氧化应激刺激的纤溶酶原激活物抑制剂1的表达。替米沙坦未改变抗氧化酶如过氧化氢酶或谷胱甘肽过氧化物酶的表达水平。此外，替米沙坦对氧化应激的改善不涉及过氧化物酶体增殖物激活受体-γ途径。结论替米沙坦至少部分以受体非依赖性方式抑制细胞内氧化应激，这可能是由于其亲脂性和抗氧化结构。
Objectives Angiotensin II plays a crucial role in the induction of oxidative stress and the pathogenesis of cardiovascular and renal diseases, and the beneficial mechanisms of angiotensin II receptor 1 blockers (ARBs) are multifactorial. We investigated the receptor-independent protective role of an ARB using primary-cultured mesangial cells from angiotensin II receptor 1 knockout or wild-type mice and a highly lipophilic ARB, telmisartan. Methods and results Intracellular reactive oxygen species were estimated using a fluorogenic probe, CM-H2DCFDA. Non-angiotensin II-induced reactive oxygen species production was generated by exposing cells to hydrogen peroxide alone or after treatment with telmisartan. Flow cytometry analysis showed that angiotensin II induced an increase in oxidant production in a dose-dependent manner in wild-type cells, but not in knockout cells. In contrast, hydrogen peroxide induced oxidative stress in both wild-type and knockout cells. Interestingly, telmisartan attenuated the oxidative stress induced by hydrogen peroxide in both cells, suggesting that it acted via a receptor-independent antioxidant effect. Intracellular concentrations of telmisartan were confirmed by high-performance liquid chromatography analysis. Expression of plasminogen activator inhibitor 1, which is stimulated by oxidative stress, was also attenuated by telmisartan in a receptor-independent as well as receptor-dependent manner. Telmisartan did not change expression levels of antioxidative enzymes such as catalase or glutathione peroxidase. Furthermore, the amelioration of oxidative stress by telmisartan did not involve the peroxisome proliferator-activated receptor-γ pathway. Conclusions Telmisartan inhibits intracellular oxidative stress, at least in part, in a receptor-independent manner, possibly owing to its lipophilic and antioxidant structure.