Comparison of ANG II with other growth factors on Egr-1 and matrix gene expression in cardiac fibroblasts
Comparison of ANG II with other growth factors on Egr-1 and matrix gene expression in cardiac fibroblasts
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DOI：
10.1152/ajpheart.1996.270.6.h2100
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发表时间：
1996-06-01
影响因子：
4.8
通讯作者：
Hsueh, WA
中科院分区：
文献类型：
--
作者：
Iwami, K;Ashizawa, N;Hsueh, WA
本研究的目的是比较血管紧张素II（ANG II）与其他生长因子的影响，这些生长因子在心室肥大中对与心脏重塑相关的心脏成纤维细胞变化起作用。这些变化包括早期生长反应（Egr-1）基因的诱导和细胞外基质蛋白的信息水平的增加。ANG II处理（10（-10）-10（-6）M）大鼠心脏成纤维细胞诱导1）Egr（-1）和c-fos，2）四倍（P < 0.02）纤维连接蛋白增加，（P = 0.05）在24-48 h时层粘连蛋白mRNA水平增加，但胶原I、III或IV水平没有增加，AT（1）受体mRNA水平在4-6 h降至基础水平的26%（P < 0.001）。这些作用均被AT（1）受体阻断剂氯沙坦抑制，但不被AT（2）受体阻断剂抑制。用抗大鼠纤连蛋白抗体对培养细胞进行免疫染色，结果显示无血清培养基中细胞染色阳性; ANG II（10（-6）M，48 h）处理的细胞染色更强。激活细胞。用抗大鼠AT（1）受体的抗体进行的分选表明，在无血清培养基中维持的细胞中存在受体信号;然而，在ANG II处理的细胞中检测不到受体信号。血清和表皮生长因子（EGF）也可诱导Egr-1的表达，而去甲肾上腺素（NE）和内皮素（ET）则无此作用。血清使纤维连接蛋白mRNA水平增加2倍（P < 0.05）。EGF、NE和ET对基质基因表达无影响。血清、EGF和NE也在处理4-6小时短暂下调AT（1）受体mRNA水平。这些结果表明：1）ANG II诱导原癌基因表达并增强培养的心脏成纤维细胞中纤连蛋白mRNA水平，而EGF仅诱导Egr-1，NE和ET对这两种功能均无影响; 2）ANG II的作用主要由AT（1）受体介导; 3）生长因子可调节AT（1）受体mRNA水平。因此，相对于NE、ET和EGF，ANG II似乎在与心脏肥大相关的成纤维细胞变化中发挥突出和直接的作用。
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.