Mizutani K, Kawashima S, Ueyama T, Sakoda T, Takeuchi S, Kobayashi S, Yokoyama M, Hayashi Y, Itoh H
Division of Surgical Pathology, Division of Cardiovascular and Respiratory Internal Medicine, Kobe University Graduate School of Medicine.
Kobe J Med Sci. 2001 Apr;47(2):47-58.
Heparan sulfate (HS) is one of the components of extracellular matrix and a potent anti-growth factor in various cells. Heparin has a similar structure to HS and is demonstrated to inhibit myocardial cell hypertrophy. We examined the intracellular signal mechanisms linking to the inhibitory effects of heparin and HS on endothelin-1 (ET-1)-induced hypertrophy in cultured rat neonatal myocardial cells (MCs). Heparin inhibited ET-1-induced c-fos mRNA expression. Heparin and HS inhibited ET-1-induced activation of c-fos promoter/enhancer in MCs. Although heparin and HS inhibited ET-1-induced activation of the wild-type c-fos serum response element (SRE), the activation of a mutated c-fos SRE that contains an intact binding site for the serum response factor (SRF) but lacks the ternary complex factor (TCF) binding site, was not inhibited. In addition, heparin and HS inhibited the activation of TPA response element (TRE). However, heparin did not inhibit the activation of cyclic AMP response element (CRE). Furthermore, heparin and HS inhibited ET-1-induced activation of extracellular signal-regulated kinase (ERK) and phosphorylation of Elk-1, which is one of the TCFs. These results indicate that heparin and HS inhibited ET-1-induced ERK activation, resulting in suppression of Elk-1 phosphorylation, and lead to inhibition of c-fos gene expression through SRF-independent manner. Moreover, heparin and HS inhibited ET-1-induced [3H] leucine incorporation. These results suggest that heparin and HS inhibit ET-1 induced myocardial cell hypertrophy through the inhibition of gene expression and protein synthesis.
硫酸乙酰肝素（HS）是细胞外基质的组成成分之一，也是多种细胞中一种有效的抗生长因子。肝素与HS结构相似，已被证明可抑制心肌细胞肥大。我们研究了与肝素和HS对培养的新生大鼠心肌细胞（MCs）中内皮素-1（ET-1）诱导的肥大的抑制作用相关的细胞内信号机制。肝素抑制ET-1诱导的c-fos mRNA表达。肝素和HS抑制ET-1诱导的MCs中c-fos启动子/增强子的激活。尽管肝素和HS抑制ET-1诱导的野生型c-fos血清反应元件（SRE）的激活，但含有血清反应因子（SRF）完整结合位点但缺乏三元复合因子（TCF）结合位点的突变型c-fos SRE的激活并未受到抑制。此外，肝素和HS抑制佛波酯反应元件（TRE）的激活。然而，肝素并不抑制环磷酸腺苷反应元件（CRE）的激活。此外，肝素和HS抑制ET-1诱导的细胞外信号调节激酶（ERK）的激活以及Elk-1（TCFs之一）的磷酸化。这些结果表明，肝素和HS抑制ET-1诱导的ERK激活，导致Elk-1磷酸化受到抑制，并通过不依赖SRF的方式抑制c-fos基因表达。此外，肝素和HS抑制ET-1诱导的[3H]亮氨酸掺入。这些结果表明，肝素和HS通过抑制基因表达和蛋白质合成来抑制ET-1诱导的心肌细胞肥大。
