Pharmacological targeting of cGAS/STING-YAP axis suppresses pathological angiogenesis and ameliorates organ fibrosis,European Journal of Pharmacology

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Pharmacological targeting of cGAS/STING-YAP axis suppresses pathological angiogenesis and ameliorates organ fibrosis
European Journal of Pharmacology ( IF 4.2 ) Pub Date : 2022-09-02 , DOI: 10.1016/j.ejphar.2022.175241
Lu Wang ₁ , Yuwei Zhang ₁ , Yafeng Ren ₂ , Xue Yang ₃ , Haijing Ben ₄ , Fulan Zhao ₃ , Sijin Yang ₅ , Li Wang ₁ , Jie Qing ₆

Affiliation

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.
Department of Pharmacy, The Affiliated Traditional Chinese Medicine Hospital of Southwest Medical University, Luzhou, 646000, Sichuan, China.
Beijing Institute of Hepatology, Beijing YouAn Hospital, Capital Medical University, Beijing, 100069, China.
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; Institute of Integrated Chinese and Western Medicine, Southwest Medical University, Luzhou, 646000, China.
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; Institute of Integrated Chinese and Western Medicine, Southwest Medical University, Luzhou, 646000, China; MOE Key Laboratory of Bioorganic Phosphorus Chemistry & Chemical Biology, Department of Chemistry, Tsinghua University, Beijing, 100084, China.

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.

中文翻译：

cGAS/STING-YAP 轴的药理学靶向抑制病理性血管生成并改善器官纤维化

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会绕过器官纤维化。环磷酸鸟苷 (GMP)-一磷酸腺苷 (AMP) 合酶 (cGAS)-干扰素基因刺激物 (STING) 信号通路与器官损伤有关，其激活可抑制内皮细胞增殖。目前，关于 cGAS/STING 激活是否会加剧炎症和组织损伤或减轻损伤，以及这些效应中的一种是否在特定情况下占主导地位，存在争议。本研究揭示了一种新的抗纤维化 cGAS/STING 信号通路，可抑制肝脏和肾脏纤维化中的病理性血管生成。我们发现 cGAS 表达在纤维化的肝脏和肾脏中被诱导，但在内皮细胞中被抑制。cGAS基因缺失促进肝肾纤维化和病理性血管生成，包括发生内皮-间质转化。同时，cGAS 缺失上调了内皮细胞中促纤维化的 Yes 相关蛋白 (YAP) 信号传导，这可以通过特异性缺乏内皮 YAP 的小鼠中器官纤维化的减弱得到证明。一种小分子 STING 激动剂 SR-717 和一种基于 G 蛋白偶联受体 (GPCR) 的拮抗剂对 cGAS/STING-YAP 信号传导的药理学靶向作用可阻断内皮 YAP 的促纤维化活性，从而减轻肝肾纤维化。总之，我们的数据支持 cGAS/STING 信号的激活减轻器官纤维化并抑制病理性血管生成。更远，

更新日期：2022-09-02

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