© 1999 American Heart Association, Inc.
Original Contributions |
Angiotensin II–Induced Transactivation of Epidermal Growth Factor Receptor Regulates Fibronectin and Transforming Growth Factor-ß Synthesis via Transcriptional and Posttranscriptional Mechanisms
From the Department of Medicine II (Y. Moriguchi, H. Matsubara, Y. Mori, S.M, H. Masaki, K.M, Y. Tsutsumi, Y.S, Y. Tanaka, T.I.), Division of Endocrine Hypertension, Metabolism and Nephrology, Kansai Medical University, Moriguchi, Osaka, and Department of Biological Science and Technology (T.N, K.O.), Science University of Tokyo, Chiba, Japan.
Correspondence to Hiroaki Matsubara, Department of Medicine II, Kansai Medical University, Fumizonocho 10-15, Moriguchi, Osaka 570-8507, Japan. E-mail: matsubah{at}takii.kmu.ac.jp
Abstract—The signaling
cascade elicited by angiotensin II (Ang II) resembles that
characteristic of a growth factor, and recent evidence indicates
transactivation of epidermal growth factor receptor (EGF-R) by G
protein–coupled receptors. Here, we report the involvement of EGF-R in
Ang II–induced synthesis of fibronectin and transforming growth
factor-ß (TGF-ß) in cardiac fibroblasts. Ang II stimulated
fibronectin mRNA levels dose dependently, with a maximal increase
(
5-fold) observed after 12 hours of incubation. Fibronectin
synthesis induced by Ang II or calcium ionophore was completely
abolished by tyrosine kinase inhibitors and intracellular
Ca2+ chelating agents. Ang II–induced fibronectin mRNA was
not affected by protein kinase C inhibitors or protein
kinase C depletion, whereas specific inhibition of EGF-R function by a
dominant negative EGF-R mutant and tyrphostin AG1478 abolished
induction of fibronectin mRNA. We isolated the rat fibronectin gene,
including the 5'-flanking region, and found that the
activator protein-1 (AP-1) binding site present in the
promoter region was responsible for the Ang II responsiveness of this
gene. A gel retardation assay revealed the binding of nuclear protein
to the AP-1 site, which was supershifted with
anti–c-fos and anti–c-jun but not
anti–activating transcription factor (ATF)-2 antibodies.
Conditioned medium from Ang II–treated cells contained TGF-ß
bioactivity, and addition of neutralizing TGF-ß antibody modestly
(46%) inhibited induction of fibronectin. Ang II–induced synthesis of
TGF-ß was also abolished by inhibition of EGF-R function. The effect
of TGF-ß was exerted by stabilizing fibronectin mRNA without
affecting the promoter activity and required de novo protein synthesis.
We concluded that Ang II–induced expression of fibronectin and TGF-ß
is mediated by downstream signaling of EGF-R transactivated by
Ca2+-dependent tyrosine kinase and that Ang II–induced
fibronectin mRNA expression is regulated by 2 different mechanisms,
which are transcriptional control by binding of the
c-fos/c-jun complex to the AP-1 site and
posttranscriptional control by mRNA stabilization due to autocrine or
paracrine effects of TGF-ß. Thus, this study suggests that the
action of Ang II on extracellular matrix formation should be
interpreted in association with the EGF-R signaling cascade.
Key Words: angiotensin II receptor • angiotensin II type 1 receptor • angiotensin II type 2 receptor • angiotensin II • epidermal growth factor receptor
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