© 2000 American Heart Association, Inc.
Molecular Medicine |
Role of NAD(P)H Oxidase in Angiotensin II–Induced JAK/STAT Signaling and Cytokine Induction
From the Department of Cardiology and Angiology, Medizinische Hochschule Hannover, Germany.
Correspondence to Bernhard Schieffer, MD, Department of Cardiology and Angiology, Medizinische Hochschule Hannover, Carl Neuberg Strasse 1, 30625 Hannover, Germany. E-mail Schieffer.Bernhard{at}MH-Hannover.de
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
(O2-) anions
activate this signaling cascade, and the vasoconstrictor angiotensin II
(Ang II) enhances the formation of
O2- 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
(AT1) receptor and induces synthesis and release
of IL-6. Therefore, we investigated the role of
O2- 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
O2- anions
determined by laser fluoroscopy, which can be abolished by DPI, a
flavoprotein inhibitor. Ang II–induced phosphorylation of JAK2,
STAT1
/ß, STAT3, and IL-6-synthesis can be abolished by DPI, as
determined by immunoprecipitations and Northern blot analysis.
Electroporation of neutralizing antisera targeted against
p47phox,
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 µmol/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
O2- anions
generated by the NAD(P)H oxidase system, and
O2-
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
O2- anions
generated by the NAD(P)H oxidase
system.
Key Words: angiotensin receptors • oxidant stress • cell signaling • atherosclerosis pathophysiology • gene regulation
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