Role of NAD(P)H Oxidase in Angiotensin II–Induced JAK/STAT Signaling and Cytokine Induction

Abstract

Abstract-Inflammatory processes involve both synthesis of inflammatory cytokines, such as interleukin-6 (IL-6), and the activation of their distinct signaling pathways, eg, the janus kinases (JAKs) and signal transducers and activators of transcription (STAT). Superoxide (O 2 Ϫ ) anions activate this signaling cascade, and the vasoconstrictor angiotensin II (Ang II) enhances the formation of O 2 Ϫ anions via the NAD(P)H oxidase system in rat aortic smooth muscle cells. Ang II activates the JAK/STAT cascade via its type 1 (AT 1 ) receptor and induces synthesis and release of IL-6. Therefore, we investigated the role of O 2 Ϫ anions generated by the NAD(P)H oxidase system on the Ang II activation of the JAK/STAT cascade and its impact on IL-6 synthesis. Ang II stimulation of rat aortic smooth muscle cells induced a rapid increase in O 2 Ϫ anions determined by laser fluoroscopy, which can be abolished by DPI, a flavoprotein inhibitor. Ang II-induced phosphorylation of JAK2, STAT1␣/␤, STAT3, and IL-6-synthesis can be abolished by DPI, as determined by immunoprecipitations and Northern blot analysis. Electroporation of neutralizing antisera targeted against p47 phox , a NAD(P)H oxidase subunit, abolished Ang II-induced JAK/STAT activation and IL-6 synthesis. Inhibition of JAK2 by its inhibitor AG490 (10 mol/L) blocked not only JAK2 activation but also IL-6 synthesis. These results suggest that stimulation of the JAK/STAT cascade by Ang II requires O 2 Ϫ anions generated by the NAD(P)H oxidase system, and O 2 Ϫ anion-dependent activation of the JAK/STAT cascade seems to be additionally involved in Ang II-induced IL-6 synthesis. Thus, Ang II-induced inflammatory effects seem to require O 2 Ϫ anions generated by the NAD(P)H oxidase system.

Thrombin Regulates Vascular Smooth Muscle Cell Growth and Heat Shock Proteins via the JAK-STAT Pathway

“…Antioxidants Inhibit Thrombin-stimulated JAK2 Phosphorylation-Reactive oxygen species (ROS)-dependent activation of JAK2 has been reported in rat VSMC treated with Ang II (45). Because thrombin also generates ROS in VSMC (58), we investigated whether antioxidants inhibit thrombin-induced activation of JAK2.…”

Angiotensin II stimulates MCP-1 production in rat glomerular endothelial cells via NAD(P)H oxidase-dependent nuclear factor-kappa B signaling

“…Recent findings have suggested that Ang II activates intracellular signaling processes, including the polyol pathway and generation of reactive oxygen species (ROS) (8,9). In cell systems, a major source of Q. Pan et al…”

Mechanism of Endothelial Cell NADPH Oxidase Activation by Angiotensin II

“…Recent studies (5) suggest that a significant source of intracellular ROS in cardiovascular cells is a phagocyte-type NADPH oxidase. AngII activates NADPH oxidases in vascular smooth muscle (5,6), fibroblasts (7), endothelial cells (EC) (8,9), and cardiomyocytes (10). Furthermore, NADPH oxidase activation and increased ROS production are implicated in AngII-stimulated vascular smooth muscle hypertrophy (3,5) and in AngII-dependent hypertension and the associated endothelial dysfunction (11)(12)(13).…”