National Traditional Chinese Medicine Clinical Research Base and Research Center of Integrated Traditional Chinese and Western Medicine, The Affiliated Traditional Chinese Medicine Hospital of Southwest Medical University, Luzhou, 646000, China.
Key Laboratory of Birth Defects and Related Diseases of Women and Children of MOE, State Key Laboratory of Biotherapy, West China Second University Hospital, Sichuan University, Chengdu, 610064, China.
Eur J Pharmacol. 2022 Oct 15;932:175241. doi: 10.1016/j.ejphar.2022.175241. Epub 2022 Sep 2.
Organ fibrosis is accompanied by pathological angiogenesis. Discovering new ways to ameliorate pathological angiogenesis may bypass organ fibrosis. The cyclic guanosine monophosphate (GMP)-adenosine monophosphate (AMP) synthase (cGAS)-stimulator of interferon genes (STING) signaling pathway has been implicated in organ injuries and its activation inhibits endothelial proliferation. Currently, a controversy exists as to whether cGAS/STING activation exacerbates inflammation and tissue injury or mitigates damage, and whether one of these effects predominates under specific context. This study unveiled a new antifibrotic cGAS/STING signaling pathway that suppresses pathological angiogenesis in liver and kidney fibrosis. We showed that cGAS expression was induced in fibrotic liver and kidney, but suppressed in endothelial cells. cGAS genetic deletion promoted liver and kidney fibrosis and pathological angiogenesis, including occurrence of endothelial-to-mesenchymal transition. Meanwhile, cGAS deletion upregulated profibrotic Yes-associated protein (YAP) signaling in endothelial cells, which was evidenced by the attenuation of organ fibrosis in mice specifically lacking endothelial YAP. Pharmacological targeting of cGAS/STING-YAP signaling by both a small-molecule STING agonist, SR-717, and a G protein-coupled receptor (GPCR)-based antagonist that blocks the profibrotic activity of endothelial YAP, attenuated liver and kidney fibrosis. Together, our data support that activation of cGAS/STING signaling mitigates organ fibrosis and suppresses pathological angiogenesis. Further, pharmacological targeting of cGAS/STING-YAP axis exhibits the potential to alleviate liver and kidney fibrosis.
器官纤维化伴随着病理性血管生成。发现改善病理性血管生成的新方法可能绕过器官纤维化。环鸟苷酸单磷酸（GMP）-腺苷酸单磷酸（AMP）合酶（cGAS）-干扰素基因刺激物（STING）信号通路已被牵连到器官损伤及其激活抑制内皮细胞增殖。目前，cGAS/STING 激活是否加剧炎症和组织损伤或减轻损伤，以及在特定情况下哪种效应占主导地位存在争议。本研究揭示了一种新的抗纤维化 cGAS/STING 信号通路，可抑制肝和肾纤维化中的病理性血管生成。我们表明，cGAS 在纤维化的肝和肾中表达被诱导，但在内皮细胞中被抑制。cGAS 基因缺失促进肝和肾纤维化和病理性血管生成，包括内皮细胞向间充质转化的发生。同时，cGAS 缺失在上皮细胞中上调了促纤维化的 Yes 相关蛋白（YAP）信号，这一点通过在特定缺乏内皮 YAP 的小鼠中减弱器官纤维化得到了证明。通过小分子 STING 激动剂 SR-717 和一种阻断内皮 YAP 促纤维化活性的 G 蛋白偶联受体（GPCR）拮抗剂对 cGAS/STING-YAP 信号的药理学靶向，均可减轻肝和肾纤维化。总之，我们的数据支持 cGAS/STING 信号的激活减轻了器官纤维化并抑制了病理性血管生成。此外，cGAS/STING-YAP 轴的药理学靶向具有减轻肝和肾纤维化的潜力。
