Endothelial cells (ECs) senescence is closely associated with the initiation and development of multiple age-related cardiovascular diseases. It is necessary to explore the underlying molecular mechanisms of ECs senescence, which is not only the basis to decipher cellular senescence, but also a novel therapeutic target for the endothelial senescence-related diseases. BRD4, a key epigenetic regulator, is universally related to gene expression regulation and has been reported to accelerate cell senescence. Besides, emerging evidence has suggested that the stimulator of interferon genes protein (STING) can regulate inflammatory and senescence-related diseases. However, whether STING pathway activation is regulated by BRD4 in the context of ECs senescence remains largely unclear. Here, we observed that elevated BRD4 and activated STING-IRF3 signaling pathway during ECs senescence and further confirmed that BRD4 could abolish STING activation. We demonstrated that BRD4 could inhibit E3 ubiquitin ligase HRD1-mediated ubiquitination degradation of STING via inhibiting HRD1 transcription. In addition to the direct regulatory effect of BRD4 on STING activation, we have confirmed that BRD4 cooperates with IRF3 and P65 to promote SASP gene expression, thereby accelerating ECs senescence. Here, we proposed a novel mechanism underlying BRD4’ key dual role in activating the STING pathway during ECs senescence.

中文翻译：

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BRD4通过激活和配合STING-IRF3通路促进LPS诱导的内皮细胞衰老

内皮细胞（EC）衰老与多种与年龄相关的心血管疾病的发生和发展密切相关。有必要探讨内皮细胞衰老的分子机制，这不仅是破译细胞衰老的基础，也是内皮衰老相关疾病的新治疗靶点。 BRD4 是一种关键的表观遗传调节因子，普遍与基因表达调控相关，据报道可加速细胞衰老。此外，新的证据表明干扰素基因蛋白刺激剂（STING）可以调节炎症和衰老相关疾病。然而，在 EC 衰老的背景下，STING 通路激活是否受到 BRD4 的调节仍不清楚。在这里，我们观察到ECs衰老过程中BRD4升高并激活STING-IRF3信号通路，并进一步证实BRD4可以消除STING激活。我们证明，BRD4 可以通过抑制 HRD1 转录来抑制 E3 泛素连接酶 HRD1 介导的 STING 泛素化降解。除了BRD4对STING激活的直接调节作用外，我们还证实BRD4与IRF3和P65协同促进SASP基因表达，从而加速ECs衰老。在此，我们提出了 BRD4 在 EC 衰老过程中激活 STING 通路的关键双重作用的新机制。