Mast cell chymase induces smooth muscle cell apoptosis by a mechanism involving fibronectin degradation and disruption of focal adhesions
Mast cell chymase induces smooth muscle cell apoptosis by a mechanism involving fibronectin degradation and disruption of focal adhesions
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DOI：
10.1161/01.atv.0000051405.68811.4d
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发表时间：
2003-02-01
影响因子：
8.7
通讯作者：
Kovanen, PT
中科院分区：
文献类型：
--
作者：
Leskinen, MJ;Lindstedt, KA;Kovanen, PT
肥大细胞释放的β-糜酶在体外可诱导血管平滑肌细胞凋亡。糜酶的蛋白水解活性是其促凋亡作用的关键，但其诱导细胞凋亡的机制尚不清楚。方法和结果--通过流式细胞仪分析、免疫组化和Western印迹，我们发现肥大细胞源性糜酶通过降解细胞外基质成分纤连蛋白（FN），随后破坏局部粘连的机制诱导SMC凋亡。FN降解产物诱导SMC凋亡的幅度相似，并与类似的变化，在由外向内的信号，糜酶。酪氨酸磷酸酶抑制剂原钒酸钠可抑制糜酶诱导的平滑肌细胞凋亡。粘着斑激酶（FAK），整合素-细胞外基质相互作用和细胞存活的关键介质之一，在糜蛋白酶或FN降解产物的存在下迅速降解。磷酸化FAK（p-FAK）的损失导致的p-FAK依赖的下游mediator Akt.Conclusions-The结果表明，分泌凝乳酶的肥大细胞可以介导凋亡的邻近SMCs通过一种机制，涉及细胞周围FN的降解和破坏的p-FAK依赖的细胞生存信号级联反应。
Objective-Chymase released from activated mast cells has been shown to induce apoptosis of vascular smooth muscle cells (SMCs) in vitro. The proteolytic activity of chymase is essential for the proapoptotic effect, but the mechanism of chymase-induced apoptosis has remained unknown. \Methods and Results-Here we show by means of FACS analysis, immunohistochemistry, and Western blotting that mast cell-derived chymase induces SMC apoptosis by a mechanism involving degradation of an extracellular matrix component, fibronectin (FN), with subsequent disruption of focal adhesions. The FN degradation products induced SMC apoptosis of similar magnitude and with similar changes in outside-in signaling, as did chymase. Sodium orthovanadate, an inhibitor of tyrosine phosphatases, inhibited the chymase-induced SMC apoptosis. Focal adhesion kinase (FAK), one of the key mediators of integrin-extracellular matrix interactions and cell survival, was rapidly degraded in the presence of chymase or FN degradation products. Loss of phosphorylated FAK (p-FAK) resulted in a rapid dephosphorylation of the p-FAK-dependent downstream mediator Akt.Conclusions-The results suggest that chymase-secreting mast cells can mediate apoptosis of neighboring SMCs through a mechanism involving degradation of pericellular FN and disruption of the p-FAK-dependent cell-survival signaling cascade.