Apoptosis of bone marrow mesenchymal stem cells caused by homocysteine via activating JNK signal.
Apoptosis of bone marrow mesenchymal stem cells caused by homocysteine via activating JNK signal.
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同型半胱氨酸激活JNK信号引起骨髓间充质干细胞凋亡
DOI：
10.1371/journal.pone.0063561
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发表时间：
2013
期刊：
影响因子：
3.7
通讯作者：
Lu Y
中科院分区：
文献类型：
--
作者：
Cai B;Li X;Wang Y;Liu Y;Yang F;Chen H;Yin K;Tan X;Zhu J;Pan Z;Wang B;Lu Y
骨髓间充质干细胞（BMSCs）具有修复受损心肌组织的功能。骨髓间充质干细胞在各种病理刺激下的凋亡导致骨髓间充质干细胞愈合能力的衰减。大量证据表明，同型半胱氨酸水平升高是心血管疾病的一个新的独立危险因素。本研究旨在探讨同型半胱氨酸是否可诱导骨髓间充质干细胞凋亡及其潜在机制。我们发现同型半胱氨酸显著抑制骨髓间充质干细胞的细胞活力。TUNEL、AO/EB、Hoechst 333342和Live/Death染色显示了同型半胱氨酸处理后骨髓间充质干细胞的凋亡形态。在同型半胱氨酸处理的骨髓间充质干细胞中，ROS水平也明显升高。DMTU和NAC阻断ROS可抑制同型半胱氨酸诱导的骨髓间充质干细胞的凋亡，提示ROS参与骨髓间充质干细胞的凋亡。此外，同型半胱氨酸还引起骨髓间充质干细胞线粒体膜电位去极化。此外，JNK抑制剂可显著逆转同型半胱氨酸处理的骨髓间充质干细胞的凋亡外观和线粒体膜电位去极化，而p38 MAPK和ERK抑制剂则不能。Western blot也证实，将骨髓间充质干细胞暴露于同型半胱氨酸后，p-JNK被显著激活。同型半胱氨酸处理导致培养基中bmscs分泌的VEGF和IGF-1显著减少。综上所述，高同型半胱氨酸升高通过ros诱导JNK信号激活诱导骨髓间充质干细胞凋亡，这为高同型半胱氨酸血症相关心血管疾病的分子机制提供了更多的见解。
Bone marrow mesenchymal stem cells (BMSCs) are capable of homing to and repair damaged myocardial tissues. Apoptosis of BMSCs in response to various pathological stimuli leads to the attenuation of healing ability of BMSCs. Plenty of evidence has shown that elevated homocysteine level is a novel independent risk factor of cardiovascular diseases. The present study was aimed to investigate whether homocysteine may induce apoptosis of BMSCs and its underlying mechanisms. Here we uncovered that homocysteine significantly inhibited the cellular viability of BMSCs. Furthermore, TUNEL, AO/EB, Hoechst 333342 and Live/Death staining demonstrated the apoptotic morphological appearance of BMSCs after homocysteine treatment. A distinct increase of ROS level was also observed in homocysteine-treated BMSCs. The blockage of ROS by DMTU and NAC prevented the apoptosis of BMSCs induced by homocysteine, indicating ROS was involved in the apoptosis of BMSCs. Moreover, homocysteine also caused the depolarization of mitochondrial membrane potential of BMSCs. Furthermore, apoptotic appearance and mitochondrial membrane potential depolarization in homocysteine-treated BMSCs was significantly reversed by JNK inhibitor but not p38 MAPK and ERK inhibitors. Western blot also confirmed that p-JNK was significantly activated after exposing BMSCs to homocysteine. Homocysteine treatment caused a significant reduction of BMSCs-secreted VEGF and IGF-1 in the culture medium. Collectively, elevated homocysteine induced the apoptosis of BMSCs via ROS-induced the activation of JNK signal, which provides more insight into the molecular mechanisms of hyperhomocysteinemia-related cardiovascular diseases.