Submitted on March 8, 2007
Accepted on July 6, 2007
Involvement of endogenous nitric oxide in angiotensin II-induced activation of vascular mitogen-activated protein kinases
Guo-Xing Zhang1, Yukiko Nagai2, Toshitaka Nakagawa2, Hiroshi Miyanaka2, Yoshihide Fujisawa2, Akira Nishiyama3, Kunihiko Izuishi4, Koji Ohmori5, and Shoji Kimura1*
1 Department of Pharmacology, KagawaUniversity Medical School, Kagawa, Japan
2 Life Science Center, KagawaUniversity, Japan
3 Department opf Pharmacology, Kagawa University Medical School, Japan
4 Department of Gastroenterological Surgery, KagawaUniversity Medical School, United States
5 Department of Cardiorenal and Cerebrovascular Medicine, KagawaUniversity Medical School, United States
* To whom correspondence should be addressed. E-mail: kimura{at}kms.ac.jp.
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 pro-arteriosclerotic 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 NG-nitro-L-arginine methyl ester (L-NAME; 5mg/kg) enhanced phosphorylation of aortic MAP kinases (ERK1/2 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, an 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/kg/min, 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.
