EA.hy926 Cells and HUVECs Share Similar Senescence Phenotypes but Respond Differently to the Senolytic Drug ABT-263.
EA.hy926 Cells and HUVECs Share Similar Senescence Phenotypes but Respond Differently to the Senolytic Drug ABT-263.
复制标题
作者：
多柔比星（DOX）诱导内皮细胞（EC）衰老，这有助于内皮功能障碍和心血管并发症。衰老清除药物选择性消除衰老细胞，以改善衰老介导的病理。以往的研究表明，永生化和原代EC模型在某些特征上存在差异。然而，在这两种模型中，尚未确定DOX诱导的衰老EC对senolytics的反应。在目前的工作中，我们首先建立了一个比较表征的DOX诱导的衰老表型在永生化EA.hy926内皮衍生细胞和原代人脐静脉EC（HUVEC）。此后，我们评估了四种衰老清除剂在两个EC中的衰老清除活性。DOX处理后，EA.hy926和HUVEC具有相似的衰老表型，其特征在于衰老标志物上调、SA-β-gal活性增加、细胞周期停滞和衰老相关分泌表型（SASP）表达升高。潜在的衰老清除药物达沙替尼、槲皮素和非瑟酮表现出对DOX诱导的衰老EA.hy926细胞和HUVEC缺乏选择性。然而，ABT-263（Navitoclax）选择性诱导DOX诱导的衰老HUVEC的细胞凋亡，但不诱导EA.hy926细胞的细胞凋亡。从机制上讲，DOX处理的EA.hy926细胞和HUVEC表现出BCL-2家族蛋白的差异表达水平。总之，EA.hy926细胞和HUVEC表现出相似的DOX诱导的衰老表型，但它们对ABT-263的反应不同，可能是由于BCL-2家族蛋白的不同表达水平。
Doxorubicin (DOX) induces endothelial cell (EC) senescence, which contributes to endothelial dysfunction and cardiovascular complications. Senolytic drugs selectively eliminate senescent cells to ameliorate senescence-mediated pathologies. Previous studies have demonstrated differences between immortalized and primary EC models in some characteristics. However, the response of DOX-induced senescent ECs to senolytics has not been determined across these two models. In the present work, we first established a comparative characterization of DOX-induced senescence phenotypes in immortalized EA.hy926 endothelial-derived cells and primary human umbilical vein EC (HUVECs). Thereafter, we evaluated the senolytic activity of four senolytics across both ECs. Following the DOX treatment, both EA.hy926 and HUVECs shared similar senescence phenotypes characterized by upregulated senescence markers, increased SA-β-gal activity, cell cycle arrest, and elevated expression of the senescence-associated secretory phenotype (SASP). The potentially senolytic drugs dasatinib, quercetin, and fisetin demonstrated a lack of selectivity against DOX-induced senescent EA.hy926 cells and HUVECs. However, ABT-263 (Navitoclax) selectively induced the apoptosis of DOX-induced senescent HUVECs but not EA.hy926 cells. Mechanistically, DOX-treated EA.hy926 cells and HUVECs demonstrated differential expression levels of the BCL-2 family proteins. In conclusion, both EA.hy926 cells and HUVECs demonstrate similar DOX-induced senescence phenotypes but they respond differently to ABT-263, presumably due to the different expression levels of BCL-2 family proteins.
登录
查看更多内容
影响因子：
9
作者：
Le Duff M;Gouju J;Jonchère B;Guillon J;Toutain B;Boissard A;Henry C;Guette C;Lelièvre E;Coqueret O
通讯作者：
Coqueret O
影响因子：
9.8
作者：
Bouis, Diane;Hospers, Geke A. P.;Mulder, Nanno H.
通讯作者：
Mulder, Nanno H.
影响因子：
5.6
作者：
Carlson, Barbara W.;Craft, Melissa A.;Benbrook, Doris M.
通讯作者：
Benbrook, Doris M.
影响因子：
20.4
作者：
Moretti, Luigi;Li, Bo;Lu, Bo
通讯作者：
Lu, Bo
影响因子：
14.9
作者：
Casella, Gabriel;Munk, Rachel;Gorospe, Myriam
通讯作者：
Gorospe, Myriam