PTEN inhibitor VO-OHpic attenuates GC-associated endothelial progenitor cell dysfunction and osteonecrosis of the femoral head via activating Nrf2 signaling and inhibiting mitochondrial apoptosis pathway
PTEN inhibitor VO-OHpic attenuates GC-associated endothelial progenitor cell dysfunction and osteonecrosis of the femoral head via activating Nrf2 signaling and inhibiting mitochondrial apoptosis pathway
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PTEN 抑制剂 VO-OHpic 通过激活 Nrf2 信号传导和抑制线粒体凋亡途径减轻 GC 相关内皮祖细胞功能障碍和股骨头坏死
DOI：
10.1186/s13287-020-01658-y
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发表时间：
2020-03
影响因子：
7.5
通讯作者：
ye yaping
中科院分区：
文献类型：
--
作者：
yao xudong;yu shengnan;jing xingzhi;guo jiachao;sun kai;guo fengjing;ye yaping
背景：糖皮质激素（GC）相关性股骨头坏死（ONFH）在非创伤性ONFH中最常见。尽管GC和ONFH之间有很强的关系，但详细的机制仍然难以捉摸。近年来的研究表明，GC可直接损伤股骨头血管，减少股骨头血供。内皮祖细胞（Endothelial progenitor cells，EPCs）在维持血管内皮正常结构和功能方面起着重要作用，但在ONFH过程中EPCs数量和功能均受到抑制。PTEN（磷酸酶和张力同源物）是一种促进细胞凋亡的肿瘤抑制基因，发现其在GC相关ONFH患者中表达升高。然而，是否直接抑制PTEN减弱GC相关的细胞凋亡和功能障碍的EPCs仍然在很大程度上是未知的。方法：我们研究了一种有效的PTEN抑制剂VO-OHpic对胃癌相关的EPCs凋亡和功能障碍的影响及其分子机制。采用SD大鼠，观察VO-OHpic对血管生成和骨坏死的影响。结果如下：结果表明，甲基强的松龙（MPS）通过诱导内皮祖细胞凋亡、破坏线粒体正常结构和功能，明显抑制内皮祖细胞血管生成。VO-OHpic治疗能够通过抑制线粒体凋亡途径和激活NF-E2相关因子2（Nrf 2）信号转导来逆转有害影响。Si-Nrf 2转染显著降低VO-OHpic对EPCs的保护作用。体内实验还表明，腹腔注射VO-OHpic可明显减轻MPS所致的股骨头坏死，并能有效地增加股骨头的血供。结论：总之，数据表明，用VO-OHpic抑制PTEN通过激活Nrf 2信号通路和抑制线粒体凋亡通路来减弱体外EPCs的凋亡并促进血管生成。此外，VO-OHpic还减轻GC相关的ONFH并增强股骨头的血管生成。
Background: Glucocorticoid (GC) associated osteonecrosis of the femoral head (ONFH) is most common in non-traumatic ONFH. Despite a strong relationship between GC and ONFH, the detailed mechanisms have remained elusive. Recent studies have shown that GC could directly injure the blood vessels and reduce blood supply in the femoral head. Endothelial progenitor cells (EPCs), which were inhibited quantitatively and functionally during ONFH, play an important role in maintaining the normal structure and function of vascular endothelium. PTEN (Phosphatase and tensin homologue) is a tumor suppressor gene that promotes cell apoptosis, and its expression was found to be elevated in GC associated ONFH patients. However, whether direct inhibition of PTEN attenuates GC associated apoptosis and dysfunction of the EPCs remains largely unknown. .Methods: We investigated the effect of, VO-OHpic, a potent inhibitor of PTEN, in attenuating GC associated apoptosis and dysfunction of EPCs and the molecular mechanism. SD rats were used to studied the of effect of VO-OHpic on angiogenesis and osteonecrosis in vivo..Results: The results revealed that methylprednisolone (MPS) obviously inhibit angiogenesis of EPCs by inducing apoptosis，destroying the normal mitochondrial structure and disrupting function of mitochondria. VO-OHpic treatment is able to reverse the harmful effects by inhibiting the mitochondrial apoptosis pathway and activating the NF-E2-related factor 2 (Nrf2) signaling. Si-Nrf2 transfection significantly reduced the protective effects of VO-OHpic on EPCs. Our in vivo studies also showed that intraperitoneal injection of VO-OHpic obviously attenuates the osteonecrosis of the femoral head induced by MPS, and potently increases the blood supply in the femoral head. .Conclusion: Taken together, the data suggests that inhibition of PTEN with VO-OHpic attenuates apoptosis and promotes angiogenesis of EPCs in vitro via activating Nrf2 signaling pathway and inhibiting the mitochondrial apoptosis pathway. Moreover, VO-OHpic also mitigates GC associated ONFH and potentiates angiogenesis the femoral head..
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影响因子：
5.3
作者：
通讯作者：
--
影响因子：
--
作者：
Jiang, Bing-Hua;Liu, Ling-Zhi
通讯作者：
Liu, Ling-Zhi
影响因子：
4.5
作者：
Meyer JN;Leuthner TC;Luz AL
通讯作者：
Luz AL
枸杞多糖通过维持线粒体裂变和融合平衡减少高血糖加重的缺血性脑损伤
影响因子：
9.2
作者：
Liu WJ;Jiang HF;Rehman FU;Zhang JW;Chang Y;Jing L;Zhang JZ
通讯作者：
Zhang JZ
人脐带间充质干细胞沃顿胶来源的外泌体通过 miR-21-PTEN-AKT 信号通路减少糖皮质激素诱导的大鼠股骨头坏死中的骨细胞凋亡
影响因子：
9.2
作者：
Kuang, Ming-jie;Huang, Ying;Ma, Xin-long
通讯作者：
Ma, Xin-long