Key result
Under basal conditions, nNOS-derived NO acts as an antioxidant reducing superoxide accumulation and suppressing vascular MAPK phosphorylation, whereas Ang II stimulation induces nNOS uncoupling.
nNOS plays a dual role in vascular tissue, acting as an antioxidant under basal conditions but uncoupling to potentiate superoxide generation under Angiotensin II stimulation.
This is the authors' abstract. We don't add key points for this paper.
AIMS: The present study is designed to investigate the role of neuronal nitric oxide synthase (nNOS) in the regulation of vascular mitogen-activated protein kinase (MAPK) activity under basal and angiotensin II (Ang II)-stimulated conditions. METHODS AND RESULTS: Incubation with a potent nNOS inhibitor (L-VNIO) significantly increased superoxide (O2(-)) levels, with increased MAPK phosphorylation, in isolated aorta and vascular smooth muscle cells (VSMCs) from wild-type mice. Both increases were inhibited by the superoxide dismutase mimetic, tempol, but not by the peroxynitrite scavenger, FeTPPS. The levels of O2(-) and MAPK phosphorylation were higher in aorta from nNOS(-/-) mice than from wild-type mice. These parameters were suppressed by tempol and oxypurinal (a xanthine oxidase inhibitor). In isolated VSMCs or aorta from wild-type mice, Ang II stimulation markedly increased the levels of O2(-) and MAPK phosphorylation. L-VNIO significantly reduced Ang II-induced increases of these parameters. Apocynin, an NAD(P)H oxidase inhibitor, further inhibited Ang II-induced increases of these parameters compared with the L-VNIO-treated group. FeTPPS did not suppress the Ang II-induced increase of O2(-) levels, but markedly inhibited Ang II-induced MAPK phosphorylation. In contrast to the wild-type, in isolated aorta or VSMCs from nNOS(-/-) mice, Ang II failed to increase O2(-) levels and MAPK phosphorylation. CONCLUSION: Under basal conditions, nNOS-derived NO acting as antioxidant reduces O2(-) accumulation and suppresses vascular MAPK phosphorylation. Under Ang II-stimulated conditions, NAD(P)H oxidase-derived O2(-), inducing nNOS uncoupling, potentiates the Ang II-induced increase of O2(-) generation. The generated O2(-) may react with NO to form peroxynitrite (ONOO(-)). Both O2(-) and ONOO(-) participate in Ang II-induced activation of vascular MAPK.
No immediate clinical implications; leaves open nNOS as a vascular target in Ang II pathways for human validation.
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Zhang et al. (2008) studied Vascular superoxide levels and MAPK phosphorylation. nNOS inhibition (L-VNIO) and Angiotensin II stimulation vs. Wild-type vs nNOS(-/-) mice; basal vs stimulated conditions was evaluated on Superoxide (O2(-)) levels and MAPK phosphorylation. Under basal conditions, nNOS-derived NO acts as an antioxidant reducing superoxide accumulation and suppressing vascular MAPK phosphorylation, whereas Ang II stimulation induces nNOS uncoupling.
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