Arteriosclerosis, Thrombosis, and Vascular Biology. 2001;21:489-495
© 2001 American Heart Association, Inc.
Vascular Biology |
Epidermal Growth Factor Receptor Transactivation by Angiotensin II Requires Reactive Oxygen Species in Vascular Smooth Muscle Cells
From the Division of Cardiology, Department of Medicine (M.U.-F., K.K.G., L.H., S.H., R.W.A.), and the Department of Physiology (P.L.B.), Emory University School of Medicine, Atlanta, Ga.
Correspondence to Masuko Ushio-Fukai, PhD, Emory University School of Medicine, Division of Cardiology, 1639 Pierce Dr, 319 WMB, Atlanta, GA 30322. E-mail mfukai{at}emory.edu
Abstract—Angiotensin
II (Ang II) is a vasoactive hormone with critical roles in vascular
smooth muscle cell growth, an important feature of hypertension and
atherosclerosis. Many of these effects are dependent on
the production of reactive oxygen species (ROS). Ang II induces
phosphorylation of the epidermal growth factor (EGF)
receptor (EGF-R), which serves as a scaffold for various signaling
molecules. Here, we provide novel evidence that ROS are critical
mediators of EGF-R transactivation by Ang II. Pretreatment of vascular
smooth muscle cells with the antioxidants diphenylene iodonium, Tiron,
N-acetylcysteine, and ebselen
significantly inhibited (
80% to 90%) tyrosine
phosphorylation of the EGF-R by Ang II but not by EGF.
Of the 5 autophosphorylation sites on the EGF-R, Ang II
mainly phosphorylated Tyr1068 and Tyr1173 in a
redox-sensitive manner. The Src family kinase inhibitor
PP1, overexpression of kinase-inactive c-Src, or chelation of
intracellular Ca2+ attenuated EGF-R
transactivation. Although antioxidants had no effects on the
Ca2+ mobilization or
phosphorylation of
Ca2+-dependent tyrosine kinase Pyk2, they
inhibited c-Src activation by Ang II, suggesting that c-Src is 1
signaling molecule that links ROS and EGF-R
phosphorylation. Furthermore, Ang II–induced tyrosine
phosphorylation of the
autophosphorylation site and the SH2 domain of c-Src
was redox sensitive. These findings emphasize the importance of ROS in
specific Ang II–stimulated growth-related signaling pathways and
suggest that redox-sensitive EGF-R transactivation may be a potential
target for antioxidant therapy in vascular
disease.
Key Words: angiotensin II • vascular smooth muscle • epidermal growth factor receptors • reactive oxygen species
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