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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M. Ushio-Fukai, Y. Tang, T. Fukai, S. I. Dikalov, Y. Ma, M. Fujimoto, M. T. Quinn, P. J. Pagano, C. Johnson, and R. W. Alexander Novel Role of gp91phox-Containing NAD(P)H Oxidase in Vascular Endothelial Growth Factor-Induced Signaling and Angiogenesis Circ. Res., December 13, 2002; 91(12): 1160 - 1167. [Abstract] [Full Text] [PDF]
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J.-J. Cheng, Y.-J. Chao, and D. L. Wang Cyclic Strain Activates Redox-sensitive Proline-rich Tyrosine Kinase 2 (PYK2) in Endothelial Cells J. Biol. Chem., December 6, 2002; 277(50): 48152 - 48157. [Abstract] [Full Text] [PDF]
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F. E. Rey and P. J. Pagano The Reactive Adventitia: Fibroblast Oxidase in Vascular Function Arterioscler Thromb Vasc Biol, December 1, 2002; 22(12): 1962 - 1971. [Abstract] [Full Text] [PDF]
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S. Saito, G. D. Frank, M. Mifune, M. Ohba, H. Utsunomiya, E. D. Motley, T. Inagami, and S. Eguchi Ligand-independent trans-Activation of the Platelet-derived Growth Factor Receptor by Reactive Oxygen Species Requires Protein Kinase C-delta and c-Src J. Biol. Chem., November 15, 2002; 277(47): 44695 - 44700. [Abstract] [Full Text] [PDF]
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T. Tanimoto, Z.-G. Jin, and B. C. Berk Transactivation of Vascular Endothelial Growth Factor (VEGF) Receptor Flk-1/KDR Is Involved in Sphingosine 1-Phosphate-stimulated Phosphorylation of Akt and Endothelial Nitric-oxide Synthase (eNOS) J. Biol. Chem., November 1, 2002; 277(45): 42997 - 43001. [Abstract] [Full Text] [PDF]
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H. Wang, J. J. Ubl, R. Stricker, and G. Reiser Thrombin (PAR-1)-induced proliferation in astrocytes via MAPK involves multiple signaling pathways Am J Physiol Cell Physiol, November 1, 2002; 283(5): C1351 - C1364. [Abstract] [Full Text] [PDF]
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Q. Che and P. K. Carmines Angiotensin II Triggers EGFR Tyrosine Kinase-Dependent Ca2+ Influx in Afferent Arterioles Hypertension, November 1, 2002; 40(5): 700 - 706. [Abstract] [Full Text] [PDF]
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P. N. Seshiah, D. S. Weber, P. Rocic, L. Valppu, Y. Taniyama, and K. K. Griendling Angiotensin II Stimulation of NAD(P)H Oxidase Activity: Upstream Mediators Circ. Res., September 6, 2002; 91(5): 406 - 413. [Abstract] [Full Text] [PDF]
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M. Ushio-Fukai, L. Hilenski, N. Santanam, P. L. Becker, Y. Ma, K. K. Griendling, and R. W. Alexander Cholesterol Depletion Inhibits Epidermal Growth Factor Receptor Transactivation by Angiotensin II in Vascular Smooth Muscle Cells. ROLE OF CHOLESTEROL-RICH MICRODOMAINS AND FOCAL ADHESIONS IN ANGIOTENSIN II SIGNALING J. Biol. Chem., December 14, 2001; 276(51): 48269 - 48275. [Abstract] [Full Text] [PDF]
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C. Berry, R. Touyz, A. F. Dominiczak, R. C. Webb, and D. G. Johns Angiotensin receptors: signaling, vascular pathophysiology, and interactions with ceramide Am J Physiol Heart Circ Physiol, December 1, 2001; 281(6): H2337 - H2365. [Abstract] [Full Text] [PDF]
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G. A. Stouffer, C. Patterson, N. Madamanchi, and M. S. Runge Role of Reactive Oxygen Species in Angiotensin II Signaling : The Plot Thickens Arterioscler Thromb Vasc Biol, April 1, 2001; 21(4): 471 - 472. [Full Text] [PDF]
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