Involvement of endogenous nitric oxide in angiotensin II-induced activation of vascular mitogen-activated protein kinases

Abstract

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 NG-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·kg−1·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.

Inducible nitric oxide synthase gene deletion exaggerates MAPK-mediated cyclooxygenase-2 induction by inflammatory stimuli

“…These findings suggest an inhibitory influence of NO on MAPK signaling that, when ablated, allows for a more robust response to inflammatory stimuli. Consistent with our observations, NO was recently shown to negatively regulate angiotensin II-elicited MAPK phosphorylation in vascular SMCs and in vivo, and exogenous peroxynitrite decreased phosphorylation of ERK1/2 and p38 in vascular SMCs (4,54,55). On the other hand, previous studies have also shown a stimulatory or biphasic role of NO-cGMP signaling on MAPK signaling (2,27,49).…”

Angiotensin II enhances EGF receptor expression levels via ROS formation in HaCaT cells

“…Studies have demonstrated that the formation of superoxide via NADPH oxidase activation by Ang II reduces NO production [30,31]. But, another study has reported that L-NAME suppresses Ang II-induced ROS formation in rat vascular smooth muscle cells [32]. Interestingly, we found that NO synthesis was not altered by Ang II, and that L-NAME did not suppress the Ang II-induced ROS formation in HaCaT cells.…”

Chemistry and Antihypertensive Effects of Tempol and Other Nitroxides

“…Tempol markedly suppressed Ang II-induced activation of vascular extracellular signal-regulated kinase (ERK) 1 and 2 and p38 (Zhang et al, 2007). This suppression was ascribed in part to an increase in NO bioactivity because it was prevented by NOS blockade (Zhang et al, 2007).…”

“…Tempol markedly suppressed Ang II-induced activation of vascular extracellular signal-regulated kinase (ERK) 1 and 2 and p38 (Zhang et al, 2007). This suppression was ascribed in part to an increase in NO bioactivity because it was prevented by NOS blockade (Zhang et al, 2007). Tempol prevented the phosphorylation of MAPKs, ERK1 and 2, c-Jun N-terminal kinase (JNK), and p38 in the aorta and heart of rats during infusions of Ang II or phenylephrine (PE) (Zhang et al, 2004a; Kimura et al, 2005a) and inhibited the phosphorylation of p38, MAPK, JNK, and ERKs in vascular tissue stimulated by Ang II or endothelin-1 (ET-1) (Touyz et al, 2004).…”