2. Academic Validation
  3. Pharmacological targeting of cGAS/STING-YAP axis suppresses pathological angiogenesis and ameliorates organ fibrosis

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

  • Eur J Pharmacol. 2022 Oct 15;932:175241. 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 6,  Jie Qing 7
Affiliations

Affiliations

  • 1 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.
  • 2 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.
  • 3 Department of Pharmacy, The Affiliated Traditional Chinese Medicine Hospital of Southwest Medical University, Luzhou, 646000, Sichuan, China.
  • 4 Beijing Institute of Hepatology, Beijing YouAn Hospital, Capital Medical University, Beijing, 100069, China.
  • 5 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.
  • 6 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. Electronic address: [email protected].
  • 7 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. Electronic address: [email protected].
PMID: 36058291 DOI: 10.1016/j.ejphar.2022.175241
Abstract

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.

Keywords

Endothelial-to-mesenchymal transition; Organ fibrosis; Pathological angiogenesis; SR-717; Yes-associated protein; cGAS/STING signaling.

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