Zhang Guo-Xing, Nagai Yukiko, Nakagawa Toshitaka, Miyanaka Hiroshi, Fujisawa Yoshihide, Nishiyama Akira, Izuishi Kunihiko, Ohmori Koji, Kimura Shoji
Department of Pharmacology, Kagawa University Medical School, Kagawa, Japan.
Am J Physiol Heart Circ Physiol. 2007 Oct;293(4):H2403-8. doi: 10.1152/ajpheart.00288.2007. Epub 2007 Jul 6.
Angiotensin II (ANG II) is a powerful activator of mitogen-activated protein (MAP) kinase cascades in cardiovascular tissues through a redox-sensitive mechanism. Nitric oxide (NO) is considered to antagonize the vasoconstrictive and proarteriosclerotic actions of ANG II. However, the role of endogenous NO in ANG II-induced redox-sensitive signal transduction is not yet clear. In this study using catheterized, conscious rats, we found that acute intravenous administration of N(G)-nitro-L-arginine methyl ester (L-NAME; 5 mg/kg) enhanced phosphorylation of aortic MAP kinases extracellular signal regulated kinase (ERK) 1/2 and p38, which were suppressed only partially by a superoxide dismutase mimetic (Tempol), whereas ANG II-induced MAP kinase phosphorylation was markedly suppressed by Tempol. FK409, a NO donor, had little effect on vascular MAP kinase phosphorylation. On the other hand, acute exposure to a vasoconstrictor dose of ANG II (200 ng x kg(-1) x min(-1) iv) failed to enhance phosphorylation of aortic MAP kinases in the chronically L-NAME-treated rats, whereas the vasoconstrictor effect of ANG II was not affected by L-NAME treatment. Furthermore, three different inhibitors of NO synthase suppressed, in a dose-dependent manner, ANG II-induced MAP kinase phosphorylation in rat vascular smooth muscle cells, which was closely linked to superoxide generation in cells. These results indicate the involvement of endogenous NO synthase in ANG II-induced signaling pathways, leading to activation of MAP kinase, and that NO may have dual effects on the vascular MAP kinase activation associated with redox sensitivity.
血管紧张素II（ANG II）通过一种氧化还原敏感机制，是心血管组织中丝裂原活化蛋白（MAP）激酶级联反应的强力激活剂。一氧化氮（NO）被认为可拮抗ANG II的血管收缩和促动脉粥样硬化作用。然而，内源性NO在ANG II诱导的氧化还原敏感信号转导中的作用尚不清楚。在本研究中，我们使用经导管插入的清醒大鼠，发现急性静脉注射N（G）-硝基-L-精氨酸甲酯（L-NAME；5 mg/kg）可增强主动脉MAP激酶细胞外信号调节激酶（ERK）1/2和p38的磷酸化，超氧化物歧化酶模拟物（Tempol）仅部分抑制了这种磷酸化，而ANG II诱导的MAP激酶磷酸化则被Tempol显著抑制。NO供体FK409对血管MAP激酶磷酸化几乎没有影响。另一方面，急性暴露于血管收缩剂量的ANG II（200 ng x kg（-1）x min（-1）静脉注射）未能增强长期L-NAME处理大鼠主动脉MAP激酶的磷酸化，而ANG II的血管收缩作用不受L-NAME处理的影响。此外，三种不同的一氧化氮合酶抑制剂以剂量依赖的方式抑制了大鼠血管平滑肌细胞中ANG II诱导的MAP激酶磷酸化，这与细胞中超氧化物的产生密切相关。这些结果表明内源性一氧化氮合酶参与了ANG II诱导的信号通路，导致MAP激酶的激活，并且NO可能对与氧化还原敏感性相关的血管MAP激酶激活具有双重作用。
