TNF-α signaling regulates RUNX1 function in endothelial cells.
TNF-α signaling regulates RUNX1 function in endothelial cells.
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TNF-α信号调节内皮细胞中的RUNX 1功能。
DOI：
10.1096/fj.202001668r
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发表时间：
2021-03
期刊：
影响因子：
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通讯作者：
Kim LA
中科院分区：
文献类型：
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作者：
Whitmore HAB;Amarnani D;O'Hare M;Delgado-Tirado S;Gonzalez-Buendia L;An M;Pedron J;Bushweller JH;Arboleda-Velasquez JF;Kim LA
Runt相关转录因子1（RUNX 1）作为异常视网膜血管生成的介质，并与增殖性糖尿病视网膜病变（PDR）的进展有关。已发现患有PDR、早产儿视网膜病变（ROP）和湿性年龄相关性黄斑变性（湿性AMD）的患者的眼中肿瘤坏死因子-α（TNF-α）水平升高。在取自PDR患者的纤维血管膜（FVM）中，血管系统中的RUNX 1表达增加，而在人视网膜微血管内皮细胞（HRMEC）中，TNF-α刺激导致RUNX 1表达增加，这可以通过RUNX 1抑制剂调节。使用TNF-α通路抑制剂，我们确定在HRMEC中，TNF-α诱导的RUNX 1表达通过JNK激活发生，而NF-κB和p38/MAPK抑制不影响RUNX 1表达。JNK抑制剂也能有效阻止高D-葡萄糖刺激的RUNX 1表达。我们进一步通过激活蛋白1（AP-1）将JNK与RUNX 1连接起来，并研究了JNK-AP-1-RUNX 1调节反馈环，该环可由VEGF调节。此外，用TNF-α和d-葡萄糖刺激对RUNX 1表达具有累加效应，其通过VEGF调节下调。这些数据表明，下调RUNX 1与抗VEGF药物联合可能在未来治疗病理性眼部血管生成疾病中很重要。
Runt‐related transcription factor 1 (RUNX1) acts as a mediator of aberrant retinal angiogenesis and has been implicated in the progression of proliferative diabetic retinopathy (PDR). Patients with PDR, retinopathy of prematurity (ROP), and wet age‐related macular degeneration (wet AMD) have been found to have elevated levels of Tumor Necrosis Factor‐alpha (TNF‐α) in the eye. In fibrovascular membranes (FVMs) taken from patients with PDR RUNX1 expression was increased in the vasculature, while in human retinal microvascular endothelial cells (HRMECs), TNF‐α stimulation causes increased RUNX1 expression, which can be modulated by RUNX1 inhibitors. Using TNF‐α pathway inhibitors, we determined that in HRMECs, TNF‐α‐induced RUNX1 expression occurs via JNK activation, while NF‐κB and p38/MAPK inhibition did not affect RUNX1 expression. JNK inhibitors were also effective at stopping high d‐glucose‐stimulated RUNX1 expression. We further linked JNK to RUNX1 through Activator Protein 1 (AP‐1) and investigated the JNK‐AP‐1‐RUNX1 regulatory feedback loop, which can be modulated by VEGF. Additionally, stimulation with TNF‐α and d‐glucose had an additive effect on RUNX1 expression, which was downregulated by VEGF modulation. These data suggest that the downregulation of RUNX1 in conjunction with anti‐VEGF agents may be important in future treatments for the management of diseases of pathologic ocular angiogenesis.