Volume 31, No 7, Jul 2021

ISSN: 1001-0602 
EISSN: 1748-7838 2018 
impact factor 17.848* 
(Clarivate Analytics, 2019)

Volume 31 Issue 7, July 2021: 773-790   |  Open Access

ORIGINAL ARTICLES

Cartilage oligomeric matrix protein is an endogenous β-arrestin-2-selective allosteric modulator of AT1 receptor counteracting vascular injury

Yi Fu¹ , Yaqian Huang^1,2 , Zhao Yang³ , Yufei Chen¹ , Jingang Zheng⁴ , Chenfeng Mao¹ , Zhiqing Li¹ , Zhixin Liu³ , Bing Yu¹ , Tuoyi Li¹ , Meili Wang¹ , Chanjuan Xu⁵ , Yiwei Zhou⁵ , Guizhen Zhao¹ , Yiting Jia¹ , Wei Guo⁶ , Xin Jia⁶ , Tao Zhang⁶ , Li Li⁷ , Ziyi Liu¹ , Shengchao Guo³ , Mingliang Ma³ , Heng Zhang¹ , Bo Liu¹ , Junbao Du² , Wengong Wang⁸ , Chaoshu Tang¹ , Pei Gao⁹ , Qingbo Xu¹⁰ , Xian Wang¹ , Jianfeng Liu⁵ , Jinpeng Sun^1,3,* , Wei Kong^1,*

¹Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Peking University; Key Laboratory of Molecular Cardiovascular Science, Ministry of Education, Beijing 100191, China
²Department of Pediatrics, Peking University First Hospital, Beijing 100034, China
³Department of Biochemistry & Molecular Biology, School of Basic Medical Sciences, Shandong University, Jinan, Shandong 250012, China
⁴Department of Cardiology, China-Japan Friendship Hospital, Beijing 100029, China
⁵College of Life Science and Technology, Collaborative Innovation Center for Brain Science, Huazhong University of Science and Technology; Key Laboratory of Molecular Biophysics, Ministry of Education, Wuhan, Hubei 430074, China
⁶Department of Vascular Surgery, Chinese PLA General Hospital, Beijing 100853, China
⁷Department of Pathology, State Key Laboratory of Cardiovascular Disease, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100037, China
⁸Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Peking University Health Science Center, Beijing 100191, China
⁹Department of Epidemiology and Biostatistics, School of Public Health, Peking University Health Science Center, Beijing 100191, China
¹⁰Cardiovascular Division, The James Black Centre, King’s College London, London SE5 9NU, UK
Correspondence: Jinpeng Sun(sunjinpeng@sdu.edu.cn)Wei Kong(kongw@bjmu.edu.cn)

Compelling evidence has revealed that biased activation of G protein-coupled receptor (GPCR) signaling, including angiotensin II (AngII) receptor type 1 (AT1) signaling, plays pivotal roles in vascular homeostasis and injury, but whether a clinically relevant endogenous biased antagonism of AT1 signaling exists under physiological and pathophysiological conditions has not been clearly elucidated. Here, we show that an extracellular matrix protein, cartilage oligomeric matrix protein (COMP), acts as an endogenous allosteric biased modulator of the AT1 receptor and its deficiency is clinically associated with abdominal aortic aneurysm (AAA) development. COMP directly interacts with the extracellular N-terminus of the AT1 via its EGF domain and inhibits AT1-β-arrestin-2 signaling, but not Gq or Gi signaling, in a selective manner through allosteric regulation of AT1 intracellular conformational states. COMP deficiency results in activation of AT1a-β-arrestin-2 signaling and subsequent exclusive AAA formation in response to AngII infusion. AAAs in COMP–/– or ApoE–/– mice are rescued by AT1a or β-arrestin-2 deficiency, or the application of a peptidomimetic mimicking the AT1-binding motif of COMP. Explorations of the endogenous biased antagonism of AT1 receptor or other GPCRs may reveal novel therapeutic strategies for cardiovascular diseases.

https://doi.org/10.1038/s41422-020-00464-8

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