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

Cell research 2021 Jul

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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.

Citation

Yi Fu, Yaqian Huang, Zhao Yang, Yufei Chen, Jingang Zheng, Chenfeng Mao, Zhiqing Li, Zhixin Liu, Bing Yu, Tuoyi Li, Meili Wang, Chanjuan Xu, Yiwei Zhou, Guizhen Zhao, Yiting Jia, Wei Guo, Xin Jia, Tao Zhang, Li Li, Ziyi Liu, Shengchao Guo, Mingliang Ma, Heng Zhang, Bo Liu, Junbao Du, Wengong Wang, Chaoshu Tang, Pei Gao, Qingbo Xu, Xian Wang, Jianfeng Liu, Jinpeng Sun, Wei Kong. Cartilage oligomeric matrix protein is an endogenous β-arrestin-2-selective allosteric modulator of AT1 receptor counteracting vascular injury. Cell research. 2021 Jul;31(7):773-790