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首页> 外文期刊>American Journal of Physiology >Matrix metalloproteinase-2 stimulates collagen-I expression through phosphorylation of focal adhesion kinase in rat cardiac fibroblasts
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Matrix metalloproteinase-2 stimulates collagen-I expression through phosphorylation of focal adhesion kinase in rat cardiac fibroblasts

机译：基质金属蛋白酶-2通过大鼠心肌成纤维细胞中粘着斑激酶的磷酸化刺激胶原蛋白I表达

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摘要

Collagen-I is thought to be the main component of the extracellular matrix in cardiac fibrosis, the accumulation of which occurs with excessive activation of matrix metalloproteinase-2 (MMP-2). MMP-2 degrades the extracellular matrix; however, the relative importance of MMP-2 to collagen-I synthesis in cardiac fibroblasts remains unclear. We investigated whether extracellular activation of MMP-2 regulates collagen-I synthesis and phosphorylation of focal adhesion kinase (FAK) in rat cardiac fibroblasts. Primary cultures of rat cardiac fibroblasts were incubated with purified active MMP-2 to determine whether extracellular MMP-2 affects collagen-I synthesis and FAK phosphorylation in cardiac fibroblasts. Exogenous MMP-2 significantly stimulated FAK (Tyr397) phosphorylation and induced collagen-I expression in a time-dependent manner. Simultaneous treatment with the FAK inhibitor PF573228 abolished exogenous MMP-2-enhanced FAK (Tyr397) phosphorylation and collagen-I expression. Cells were then stimulated with norepi-nephrine (NE) to investigate whether endogenous MMP-2 could also induce collagen-I expression through FAK (Tyr397) phosphorylation. NE-stimulated endogenous MMP-2 activation in conditioned medium was significantly attenuated by simultaneous treatment with the MMP inhibitor PD166793. Similarly, NE-induced FAK (Tyr397) phosphorylation and collagen-I expression were significantly inhibited by simultaneous treatment with PD166793 or PF573228. Furthermore, MMP-2 knockdown induced by small interfering RNA (siRNA) significantly abolished endogenous MMP-2 expression and activation. MMP-2 siRNA significantly abolished NE-induced FAK (Tyr397) phosphorylation and collagen-I expression. These findings suggest that the extracellular activation of MMP-2 accelerated collagen-I synthesis in rat cardiac fibroblasts and that FAK phosphorylation (Tyr397) plays a pivotal role in MMP-2-stimulated collagen-I synthesis.
机译：胶原蛋白I被认为是心脏纤维化中细胞外基质的主要成分，其积累是由于基质金属蛋白酶2（MMP-2）的过度活化而发生的。 MMP-2降解细胞外基质;然而，尚不清楚MMP-2对心脏成纤维细胞中胶原蛋白I合成的相对重要性。我们调查了MMP-2的细胞外激活是否调节大鼠心脏成纤维细胞中的胶原蛋白I合成和粘着斑激酶（FAK）的磷酸化。将大鼠心脏成纤维细胞的原代培养物与纯化的活性MMP-2孵育，以确定细胞外MMP-2是否影响心脏成纤维细胞中的胶原蛋白I合成和FAK磷酸化。外源MMP-2以时间依赖性方式显着刺激FAK（Tyr397）磷酸化并诱导胶原蛋白I表达。用FAK抑制剂PF573228同时治疗消除了外源性MMP-2增强的FAK（Tyr397）磷酸化和胶原蛋白I的表达。然后用去甲肾上腺素（NE）刺激细胞，以研究内源性MMP-2是否也可以通过FAK（Tyr397）磷酸化诱导胶原I表达。通过同时用MMP抑制剂PD166793处理，NE刺激的条件培养基中的内源性MMP-2活化显着减弱。同样，通过同时用PD166793或PF573228处理，NE诱导的FAK（Tyr397）磷酸化和胶原蛋白I表达被显着抑制。此外，由小干扰RNA（siRNA）诱导的MMP-2敲低显着消除了内源性MMP-2的表达和激活。 MMP-2 siRNA显着消除了NE诱导的FAK（Tyr397）磷酸化和胶原蛋白I的表达。这些发现表明，MMP-2的细胞外激活促进了大鼠心脏成纤维细胞中胶原蛋白I的合成，而FAK磷酸化（Tyr397）在MMP-2刺激的胶原蛋白I合成中起着关键作用。

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