PAR1‑mediated c‑Jun activation promotes heat stress‑induced early stage apoptosis of human umbilical vein endothelial cells.
PAR1‑mediated c‑Jun activation promotes heat stress‑induced early stage apoptosis of human umbilical vein endothelial cells.
复制标题
PAR1介导的c-Jun激活促进热应激诱导的人脐静脉内皮细胞早期凋亡
DOI：
10.3892/mmr.2017.6303
复制
发表时间：
2017-05
影响因子：
3.4
通讯作者：
Su L
中科院分区：
文献类型：
--
作者：
Zhang S;Liu Y;Wang Z;Liu J;Gu Z;Xu Q;Su L
我们之前的研究表明，当参与内皮屏障功能的人脐静脉内皮细胞（HUVEC）受到热应激时，蛋白酶激活受体1（PAR1）的水平显着增加。本研究表明，PAR1 在热应激诱导的 HUVEC 细胞凋亡中发挥着至关重要的作用。当使用 PAR1 抑制剂 SCH79797 (SCH) 或靶向 PAR1 的小干扰 RNA (siRNA) 抑制 PAR1 信号传导时，细胞凋亡、caspase-3 活性和促凋亡蛋白 B 细胞淋巴瘤 2 (Bcl-2) 相关 X (Bax) 的表达显着降低，并且抗凋亡 Bcl-2 家族成员骨髓细胞白血病 1 的表达增加(Mcl-1)，被观察到。此外，在给予PAR1激动剂、TFLLR-NH2或PAR1腺病毒过表达后，热应激诱导的细胞凋亡、caspase-3活性和Bax表达显着增加。这伴随着 Mcl-1 蛋白表达水平的降低。此外，在热应激诱导的 HUVEC 中，由于 SCH 抑制 PAR1 信号传导或 siRNA 介导的 PAR1 敲低，核因子 (NF)-κB p65 亚基的 DNA 结合活性增加，c-Jun 激活减少。此外，我们之前的研究报告称，NF-κB p65 激活可能对热应激 HUVEC 具有抗凋亡作用，而在本研究中，c-Jun 激活对热应激 HUVEC 具有促凋亡作用。综上所述，这些结果表明 PAR1 信号介导的 c-Jun 激活促进热应激诱导的 HUVEC 细胞早期凋亡。
Our previous study indicated that when human umbilical vein endothelial cells (HUVECs), which are involved in endothelial barrier function, are heat stressed, levels of protease-activated receptor 1 (PAR1) are increased significantly. In the present study, it was demonstrated that PAR1 serves a vital role in heat stress-induced HUVEC apoptosis. When the PAR1 inhibitor, SCH79797 (SCH), or a small interfering RNA (siRNA) targeting PAR1 were used to inhibit PAR1 signaling, a marked decrease in cell apoptosis, caspase-3 activity and the expression of the pro-apoptotic protein B-cell lymphoma 2 (Bcl-2) associated X (Bax), as well as increased expression of the anti-apoptotic Bcl-2 family member, myeloid cell leukemia 1 (Mcl-1), were observed. In addition, heat stress-induced apoptosis, caspase-3 activity and the expression of Bax were significantly increased following administration of the PAR1 agonist, TFLLR-NH2 or adenovirus overexpression of PAR1. This was accompanied by decreased protein expression levels of Mcl-1. Furthermore, it was identified that the DNA binding activity of the nuclear factor (NF)-κB p65 subunit increased and c-Jun activation was reduced as a result of inhibition of PAR1 signaling by SCH or siRNA-mediated PAR1 knockdown in heat stress-induced HUVECs. Additionally, our previous study reported that NF-κB p65 activation may have an anti-apoptosis effect on heat stressed HUVECs, whereas in the present study c-Jun activation had a pro-apoptosis effect on heat stressed HUVECs. Taken together, these results indicated that PAR1 signaling-mediated c-Jun activation promotes early apoptosis of HUVEC cells induced by heat stress.