Recombinant tissue factor pathway inhibitor induces apoptosis in cultured rat mesangial cells via its Kunitz-3 domain and C-terminal through inhibiting PI3-kinase/Akt pathway
Recombinant tissue factor pathway inhibitor induces apoptosis in cultured rat mesangial cells via its Kunitz-3 domain and C-terminal through inhibiting PI3-kinase/Akt pathway
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重组组织因子途径抑制剂通过抑制 PI3 激酶/Akt 途径，通过其 Kunitz-3 结构域和 C 末端诱导培养的大鼠系膜细胞凋亡
DOI：
10.1007/s10495-007-0136-y
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发表时间：
2007-12-01
期刊：
影响因子：
7.2
通讯作者：
Ma, Duan
中科院分区：
文献类型：
--
作者：
Lin, Yi-feng;Zhang, Nong;Ma, Duan
组织因子途径抑制物（TFPI）是组织因子（TF）诱导凝血的内源性抑制物。TFPI除具有抗凝活性外，还具有抗增殖、诱导凋亡等作用。本研究旨在探讨TFPI是否诱导大鼠系膜细胞凋亡及其可能的信号通路。Hoechst 33258法、流式细胞术、DNA核小体梯移、caspase 3法等研究表明，重组TFPI（rTFPI）通过其Kunitz-3结构域和C端诱导培养的MsCs凋亡，且呈剂量和时间依赖性。由于丝氨酸/苏氨酸蛋白激酶Akt作为MsCs中的存活（抗凋亡）信号的介导者而引起关注，我们研究了磷酸化Akt及其下游信号磷酸化I κB-α和一些其他信号分子如Fas和bcl-2的表达。结果提示rTFPI诱导的大鼠MsCs凋亡过程至少部分是通过PI 3-Kinase-Akt信号通路进行的，而不是通过与组织因子结合。我们的研究结果表明，rTFPI在诱导炎症条件下的MsCs凋亡的潜在用途。
Tissue factor pathway inhibitor (TFPI) is an endogenous inhibitor of tissue factor (TF) induced coagulation. In addition to its anticoagulation activity, TFPI has other functions such as antiproliferation and inducing apoptosis. In the present study, we investigated whether or not TFPI induced apoptosis in cultured rat mesangial cells (MsCs) and the possible signal pathway that involved in the apoptotic process. We demonstrated that recombinant TFPI (rTFPI) induced apoptosis in cultured MsCs via its Kunitz-3 domain and C-terminal in a dose- and time-dependent manner by Hoechst 33258 assay, flow cytometry, nucleosomal laddering of DNA, caspase 3 assay. Because the serine/threonine protein kinase Akt has attracted attention as a mediator of survival (anti-apoptotic) signal in MsCs, we investigated the expression of phosphospecific-Akt and its downstream signal phospho-IκB-α and some other signal molecules like Fas and bcl-2. The results indicated that the process of apoptosis triggered by rTFPI is, at least in part, actively conducted by rat MsCs possibly through PI3-Kinase-Akt signal pathway not by binding to tissue factor. Our findings suggest that rTFPI has the potential usefulness in inducing apoptosis of MsCs under inflammatory conditions.