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

ABSTRACT: 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.

SUBMITTER: Fu Y

PROVIDER: S-EPMC8249609 | biostudies-literature | 2021 Jul

REPOSITORIES: biostudies-literature

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

Fu Yi Y Huang Yaqian Y Yang Zhao Z Chen Yufei Y Zheng Jingang J Mao Chenfeng C Li Zhiqing Z Liu Zhixin Z Yu Bing B Li Tuoyi T Wang Meili M Xu Chanjuan C Zhou Yiwei Y Zhao Guizhen G Jia Yiting Y Guo Wei W Jia Xin X Zhang Tao T Li Li L Liu Ziyi Z Guo Shengchao S Ma Mingliang M Zhang Heng H Liu Bo B Du Junbao J Wang Wengong W Tang Chaoshu C Gao Pei P Xu Qingbo Q Wang Xian X Liu Jianfeng J Sun Jinpeng J Kong Wei W

Cell research 20210128 7

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 ...[more]

PMID: 33510386

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Project description:Background & aimsLiver fibrosis is characterized by significant accumulation of extracellular matrix (ECM) proteins, mainly fibrillar collagen-I, as a result of persistent liver injury. Cartilage oligomeric matrix protein (COMP) is largely found in the ECM of skeletal tissue. Increased COMP expression has been associated with fibrogenesis in systemic sclerosis, lung fibrosis, chronic pancreatitis, cirrhosis and hepatocellular carcinoma. We hypothesized that COMP could induce fibrillar collagen-I deposition and participate in matrix remodeling thus contributing to the pathophysiology of liver fibrosis.MethodsThioacetamide (TAA) and carbon tetrachloride (CCl4) were used to induce liver fibrosis in wild-type (WT) and Comp-/- mice. In vitro experiments were performed with primary hepatic stellate cells (HSCs).ResultsCOMP expression was detected in livers from control WT mice and was upregulated in response to either TAA or CCl4-induced liver fibrosis. TAA-treated or CCl4-injected Comp-/- mice showed less liver injury, inflammation and fibrosis compared to their corresponding control WT mice. Challenge of HSCs with recombinant COMP (rCOMP) induced intra- plus extracellular collagen-I deposition and increased matrix metalloproteinases (MMPs) 2, 9 and 13, albeit similar expression of transforming growth factor beta (TGFβ) protein, in addition to Tgfβ, tumour necrosis factor alpha (Tnfα) and tissue inhibitor of metalloproteinases-1 (Timp1) mRNAs. We demonstrated that COMP binds collagen-I; yet, it does not prevent collagen-I cleavage by MMP1. Last, rCOMP induced collagen-I expression in HSCs via CD36 receptor signaling and activation of the MEK1/2-pERK1/2 pathway.ConclusionThese results suggest that COMP contributes to liver fibrosis by regulating collagen-I deposition.Lay summaryCartilage oligomeric matrix protein (COMP) induces fibrillar collagen-I deposition via the CD36 receptor signaling and activation of the MEK1/2-pERK1/2 pathway, and participates in extracellular matrix remodeling contributing to the pathophysiology of liver fibrosis.

Dataset Information

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

Publications

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

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