Cartilage oligomeric matrix protein is an endogenous β-arrestin-2-selective allosteric modulator of AT1 receptor counteracting vascular injury.
Cartilage oligomeric matrix protein is an endogenous β-arrestin-2-selective allosteric modulator of AT1 receptor counteracting vascular injury.
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软骨寡聚基质蛋白是 AT1 受体的内源性 β-arrestin-2 选择性变构调节剂，可抵抗血管损伤
DOI：
10.1038/s41422-020-00464-8
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发表时间：
2021-07
期刊：
影响因子：
44.1
通讯作者：
Kong W
中科院分区：
文献类型：
--
作者：
Fu Y;Huang Y;Yang Z;Chen Y;Zheng J;Mao C;Li Z;Liu Z;Yu B;Li T;Wang M;Xu C;Zhou Y;Zhao G;Jia Y;Guo W;Jia X;Zhang T;Li L;Liu Z;Guo S;Ma M;Zhang H;Liu B;Du J;Wang W;Tang C;Gao P;Xu Q;Wang X;Liu J;Sun J;Kong W
令人信服的证据表明，偏激活G蛋白偶联受体（GPCR）信号，包括血管紧张素II（AngII）受体1型（AT 1）信号，在血管稳态和损伤中起着关键作用，但是否有临床相关的内源性偏拮抗AT 1信号在生理和病理生理条件下存在尚未明确阐明。在这里，我们表明，细胞外基质蛋白，软骨寡聚基质蛋白（COMP），作为一种内源性变构偏置的调节剂的AT 1受体和它的缺陷在临床上与腹主动脉瘤（AAA）的发展。COMP通过其EGF结构域直接与AT 1的细胞外N-末端相互作用，并通过AT 1细胞内构象状态的变构调节以选择性方式抑制AT 1-β-arrestin-2信号传导，但不抑制Gq或Gi信号传导。COMP缺陷导致AT 1a-β-arrestin-2信号传导激活，随后响应AngII输注形成排他性AAA。COMP-/-或ApoE-/-小鼠中的AAAs可通过AT 1a或β-arrestin-2缺陷或应用模拟COMP的AT 1结合基序的肽模拟物来拯救。探索AT 1受体或其他GPCR的内源性偏向性拮抗作用可能会揭示心血管疾病的新治疗策略。
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 inCOMP–/–orApoE–/–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.
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