Comparison of angiotensin ii with other growth factors on egr-1 and
matrix gene expression in cardiac fibroblasts.
Iwami, Koichi, Naoto Ashizawa, Yung S. Do, Kristof Graf, Willa A.
Hsueh.
Department of Medicine, Division of Endocrinology, Diabetes and
Hypertension, University of Southern California, School of Medicine,
Los Angeles, CA 90033
APStracts 3:0031H, 1996.
The purpose of the present investigation was to compare the effects of
angiotensin II (AII) vs other growth factors implicated to play a
role in ventricular hypertrophy on cardiac fibroblast changes
associated with cardiac remodeling. These changes included induction
of early growth response (Egr-1) gene and increases in message levels
of extracellular matrix proteins. AII treatment (10-10-10-6M) of rat
cardiac fibroblasts induced: 1) Egr-1 and c-fos 2) a 4-fold
(p<0.02) increase in fibronectin and a 2-fold (p=0.05) increase
in laminin mRNA levels but no increases in that of collagens I, III
or IV at 24-48h and 3) a decrease in AT1 receptor mRNA levels to 26%
(p<0.001) of basal at 4-6h. These effects were all inhibited by
the AT1 receptor blocker, losartan, but not AT2 receptor blockers.
Immunostaining of cultured cells with antibody against rat
fibronectin demonstrated positive staining of cells in serum free
media; staining was more intense in cells treated with AII (10-6M,
48h). Fluorescent activated cell sorting (FACS) using an antibody
against rat AT1 receptor demonstrated a receptor signal in cells
maintained in serum free media; however, the receptor signal was not
detectable in AII treated cells. Serum and epidermal growth factor
(EGF) also induced Egr-1, but norepinephrine (NE) and endothelin (ET)
had no effect. Serum increased fibronectin mRNA levels by 2-fold
(p<0.05). EGF, NE, and ET had no effect on matrix gene
expression. Serum, EGF, and NE also transiently downregulated AT1
receptor mRNA levels at 4-6h of treatment. These results demonstrate
that 1) AII both induces protooncogene expression and enhances
fibronectin mRNA levels in cultured cardiac fibroblasts, while EGF
only induces Egr-1 and NE and ET have no effects on either function;
2) AII effects are primarily mediated by the AT1 receptor, and 3)
growth factors can regulate AT1 receptor mRNA levels. Thus AII,
relative to NE, ET and EGF, appears to play a prominent and direct
role in fibroblast changes associated with cardiac hypertrophy.
Received 23 March 1995; accepted in final form 18 September 1995.
APS Manuscript Number H284-5.
Article publication pending Am. J. Physiol. (Heart Circ. Physiology).
ISSN 1080-4757 Copyright 1996 The American Physiological Society.
Published in APStracts on 25 January 96