Comparison of ANG II with other growth factors on Egr-1 and matrix gene expression in cardiac fibroblasts

被引:46
作者
Iwami, K [1 ]
Ashizawa, N [1 ]
Do, YS [1 ]
Graf, K [1 ]
Hsueh, WA [1 ]
机构
[1] UNIV SO CALIF, SCH MED, DEPT MED, DIV ENDOCRINOL DIABET & HYPERTENS, LOS ANGELES, CA 90033 USA
来源
AMERICAN JOURNAL OF PHYSIOLOGY-HEART AND CIRCULATORY PHYSIOLOGY | 1996年 / 270卷 / 06期
关键词
fibronectin; losartan;
D O I
10.1152/ajpheart.1996.270.6.H2100
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
The purpose of the present investigation was to compare the effects of angiotensin II (ANG II) 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. ANG II treatment (10(-10)-10(-6) M) of rat cardiac fibroblasts induced 1) Egr(-1) and c-fos, 2) a fourfold (P < 0.02) increase in fibronectin and a twofold (P = 0.05) increase in laminin mRNA levels but no increases in that of collagens I, III, or IV at 24-48 h, and 3) a decrease in AT(1)-receptor mRNA levels to 26% (P < 0.001) of basal at 4-6 h. These effects were all inhibited by the AT(1)-receptor blocker, losartan, but not AT(2)-receptor blockers. Immunostaining of cultured cells with antibody against rat fibronectin demonstrated positive staining of cells in serum-free medium; staining was more intense in cells treated with ANG II (10(-6) M, 48 h). Fluorescent-activated cell. sorting using an antibody against rat AT(1) receptor demonstrated a receptor signal in cells maintained in serum-free medium; however, the receptor signal was not detectable in ANG II-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 twofold (P < 0.05). EGF, NE, and ET had no effect on matrix gene expression. Serum, EGF, and NE also transiently downregulated AT(1)-receptor mRNA levels at 4-6 h of treatment. These results demonstrate that 1) ANG II both induces protooncogene expression and enhances fibronectin mRNA levels in cultured cardiac fibroblasts, whereas EGF only induces Egr-1, and NE and ET have no effects on either function; 2) ANG II effects are primarily mediated by the AT(1) receptor; and 3) growth factors can regulate AT(1)-receptor mRNA levels. Thus ANG II, relative to NE, ET, and EGF, appears to play a prominent and direct role in fibroblast changes associated with cardiac hypertrophy.
引用
收藏
页码:H2100 / H2107
页数:8
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