人血管内皮抑素诱导内皮细胞凋亡的机理研究
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摘要
血管内皮抑制素自1997年被分离和发现以后,引起了世界各国科学家极大的研究兴趣,目前有上千篇文章关于血管内皮抑制素的各种报道,研究范围覆盖生物活性、蛋白结构与功能、作用分子机理等。血管内皮抑制素能够在体内外抑制肿瘤新生血管生成,目前已成为临床治疗肿瘤的最有效的内源性血管生成抑制剂类分子之一。血管内皮抑制素能够诱导内皮细胞发生凋亡,被认为是其抑制新生血管生成的重要机理之一。但是,目前对于这一过程的具体分子机理还不是非常清楚。在本文的研究中,我们通过研究血管内皮抑素诱导的内皮细胞凋亡,试图阐明在内皮细胞内与凋亡相关的信号转导通路及分子作用机理。我们证明血管内皮抑制素能够诱导人微血管内皮细胞在体外发生凋亡,诱导细胞色素c释放到细胞浆中,激活下游的Caspase-9。同时,细胞内ATP水平减少、线粒体跨膜电位降低、细胞内活性氧的产生等实验证明线粒体失活参与了凋亡的调控。进一步研究发现血管内皮抑素诱导线粒体通透性转变孔开放,而线粒体外膜上的VDAC1蛋白在调控开放过程中发挥重要作用,血管内皮抑素诱导VDAC1蛋白量增加。当我们干扰VDAC1后,发现血管内皮抑素的促凋亡作用受到抑制。而过量表达VDAC1后,Caspase-9的激活,活性氧的释放等凋亡事件发生的几率增加,证明VDAC1在血管内皮抑素促进细胞凋亡的过程中发挥重要的调控作用。同时,我们发现血管内皮抑素能够诱导己糖激酶HK2表达量下调,诱发了VDAC1的蛋白量上调以及相应的细胞凋亡。我们进一步证明血管内皮抑素诱导VDAC1发生磷酸化,VDAC1上的Ser-12, Ser-103可能是发生磷酸化的位点。功能实验证明,Ser-12和Ser-103的去磷酸化突变体抑制血管内皮抑素诱导的VDAC1的蛋白量的增加、线粒体通透性转变孔的开放和Caspase-3的激活,证明了VDAC1的磷酸化在血管内皮抑素诱导凋亡中所起的关键作用。我们的研究完善了对于血管内皮抑素诱导的内皮细胞凋亡机理的理解,对抗新生血管生成药物的临床应用具有一定的指导意义。
Endostatin is a proteolytic fragment of the C-terminal of collagen XVIII. Since its discovery in 1997, there are more than 1000 papers published on endostatin. It has been found that endostatin can inhibit angiogenesis in vitro and in vivo. Moreover, endostatin has potent therapeutic effect as one of the most powerful endogenous angiogenesis inhibitors in clinical studies.
Though the pro-apoptotic activity of endostatin is predictable to its anti-angiogenic function, the exact mechanism remains controversial. In the present study, we elucidate the mechanism of endostatin-induced endothelial cell apoptosis. Our results show that endostatin induces apoptosis in human microvascular endothelial cells (HMECs). In addition, endostatin induces cytochrome c release and caspase-9 activation, which initiate that the apoptosis process is involved in mitochondria. Further ATP production, mitochondrial membrane potential, ROS release and tubule formation assays show that endostatin promotes the mitochondrial permeability transition pore (mPTP) opening via voltage dependent anion channel 1 (VDAC1), a major component of mitochondrial outer membrane. Knocking down VDAC1 attenuates endostatin-induced apoptosis, while over-expression of VDAC1 enhances the sensitivity of endothelial cells to endostatin. These results indicate VDAC1 play an important role in regulating endostatin-induced endothelial cell apoptosis. Moreover, we reveal that endostatin induces the reduction of hexokinase 2, which in turn promotes VDAC1 accumulation and the subsequent apoptosis. We also show that endostatin induces VDAC1 phosphorylation, which may inhibit the degradation of intracellular VDAC1. Further mPTP opening and caspase-3 activation assays indicate that two serine residues of VDAC1, Ser-12 and Ser-103, can modulate VDAC1 protein level and thus the sensitivity to apoptosis stimuli. Our findings are novel and significant, and will have a strong impact to the understanding of the molecular mechanisms of angiogenesis inhibitors such as endostatin. Furthermore, the identification of VDAC1 and HK2 in angiogenesis regulation provides more potential targets for anti-cancer therapeutics.
Endostatin is a proteolytic fragment of the C-terminal of collagen XVIII. Since its discovery in 1997, there are more than 1000 papers published on endostatin. It has been found that endostatin can inhibit angiogenesis in vitro and in vivo. Moreover, endostatin has potent therapeutic effect as one of the most powerful endogenous angiogenesis inhibitors in clinical studies.
Though the pro-apoptotic activity of endostatin is predictable to its anti-angiogenic function, the exact mechanism remains controversial. In the present study, we elucidate the mechanism of endostatin-induced endothelial cell apoptosis. Our results show that endostatin induces apoptosis in human microvascular endothelial cells (HMECs). In addition, endostatin induces cytochrome c release and caspase-9 activation, which initiate that the apoptosis process is involved in mitochondria. Further ATP production, mitochondrial membrane potential, ROS release and tubule formation assays show that endostatin promotes the mitochondrial permeability transition pore (mPTP) opening via voltage dependent anion channel 1 (VDAC1), a major component of mitochondrial outer membrane. Knocking down VDAC1 attenuates endostatin-induced apoptosis, while over-expression of VDAC1 enhances the sensitivity of endothelial cells to endostatin. These results indicate VDAC1 play an important role in regulating endostatin-induced endothelial cell apoptosis. Moreover, we reveal that endostatin induces the reduction of hexokinase 2, which in turn promotes VDAC1 accumulation and the subsequent apoptosis. We also show that endostatin induces VDAC1 phosphorylation, which may inhibit the degradation of intracellular VDAC1. Further mPTP opening and caspase-3 activation assays indicate that two serine residues of VDAC1, Ser-12 and Ser-103, can modulate VDAC1 protein level and thus the sensitivity to apoptosis stimuli. Our findings are novel and significant, and will have a strong impact to the understanding of the molecular mechanisms of angiogenesis inhibitors such as endostatin. Furthermore, the identification of VDAC1 and HK2 in angiogenesis regulation provides more potential targets for anti-cancer therapeutics.
引文
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