Plasminogen K5 activates mitochondrial apoptosis pathway in endothelial cells by regulating Bak and Bcl-xL subcellular distribution
Plasminogen K5 activates mitochondrial apoptosis pathway in endothelial cells by regulating Bak and Bcl-xL subcellular distribution
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DOI：
10.1007/s10495-011-0618-9
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发表时间：
2011-08-01
期刊：
影响因子：
7.2
通讯作者：
Yang, Xia
中科院分区：
文献类型：
--
作者：
Gu, Xiaoqiong;Yao, Yachao;Yang, Xia
纤溶酶原Kringle 5（K5）是纤溶酶原的蛋白水解片段，其显示出有效的抗血管生成活性。K5已显示在增殖的内皮细胞中诱导细胞凋亡;然而，确切的机制尚未被很好地探索。本研究旨在阐明K5诱导内皮细胞凋亡的可能分子机制。我们的研究结果表明，K5抑制人脐静脉内皮细胞（HUVECs）中激活的碱性成纤维细胞生长因子，表明以剂量依赖性方式增殖，并通过凋亡诱导内皮细胞死亡。K5暴露活化半胱天冬酶7、8和9。这些结果提示，K5诱导的细胞凋亡可能既有线粒体内源性凋亡途径，也有线粒体外源性凋亡途径。K5降低HUVECs的线粒体膜电位（MMP），证明HUVECs中的线粒体去极化。K5使线粒体上巴克与Bcl-x（L）的比值增加，胞浆中的比值降低，但对这些蛋白的总量无影响。K5对Bax/Bcl-2分布无影响。K5增加线粒体上的巴克与Bcl-x（L）的比率，导致线粒体去极化、细胞色素c释放，并因此导致半胱天冬酶9的切割。这些结果表明，K5至少部分通过激活线粒体凋亡途径诱导内皮细胞凋亡。K5对巴克和Bcl-x（L）分布的调节可能在内皮细胞凋亡中起重要作用。这些结果为K5在血管生成相关的眼部疾病和实体瘤中的抗血管生成作用提供了进一步的见解。
Plasminogen Kringle 5(K5) is a proteolytic fragment of plasminogen, which displays potent anti-angiogenic activities. K5 has been shown to induce apoptosis in proliferating endothelial cells; however the exact mechanism has not been well explored. The present study was designed to elucidate the possible molecular mechanism of K5-induced endothelial cell apoptosis. Our results showed that K5 inhibited basic fibroblast growth factors activated in human umbilical vein endothelial cells (HUVECs), indicating proliferation in a dose-dependent manner and induced endothelial cell death via apoptosis. K5 exposure activated caspase 7, 8 and 9. These results suggested that both the intrinsic mitochondrial apoptosis pathway and extrinsic pathway might be involved in K5-induced apoptosis. K5 reduced mitochondrial membrane potential (MMP) of HUVECs, demonstrating mitochondrial depolarization in HUVECs. K5 increased the ratio of Bak to Bcl-x(L) on mitochondria, decreased the ratio in cytosol, and had no effect on the total amounts of these proteins. K5 also did not effect on Bax/Bcl-2 distribution. K5 increased the ratio of Bak to Bcl-x(L) on mitochondrial that resulted in mitochondrial depolarization, cytochrome c release and consequently the cleavage of caspase 9. These results suggested that K5 induces endothelial cell apoptosis at least in part via activating mitochondrial apoptosis pathway. The regulation of K5 on Bak and Bcl-x(L) distribution may play an important role in endothelial cell apoptosis. These results provide further insight into the anti-angiogenesis roles of K5 in angiogenesis-related ocular diseases and solid tumors.