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

Fu, Yi; Huang, Yaqian; Yang, Zhao; Chen, Yufei; Zheng, Jingang; Mao, Chenfeng; Li, Zhiqing; Liu, Zhixin; Yu, Bing; Li, Tuoyi; Wang, Meili; Xu, Chanjuan; Zhou, Yiwei; Zhao, Guizhen; Jia, Yiting; Guo, Wei; Jia, Xin; Zhang, Tao; Li, Li; Liu, Ziyi; Guo, Shengchao; Ma, Mingliang; Zhang, Heng; Liu, Bo; Du, Junbao; Wang, Wengong; Tang, Chaoshu; Gao, Pei; Xu, Qingbo; Wang, Xian; Liu, Jianfeng; Sun, Junying; Kong, Wei

doi:10.1038/s41422-020-00464-8

Cited by 34 publications

(29 citation statements)

References 82 publications

(119 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Yi Fu et al found that it could act as an endogenous β-arrestin-2-selective allosteric modulator of AT1 receptor counteracting vascular injury. Its de ciency aggravated AngII-induced AAA formation [51]. Thrombospondin-1 (Thbs1) also is a matricellular protein involved in the maintenance of vascular structure and homeostasis through the regulation of cell proliferation, apoptosis, and adhesion.…”

Section: Discussionmentioning

confidence: 99%

Single-cell RNA Sequencing Technology Revealed the Pivotal Role of Fibroblast Heterogeneity in Ang II-Induced Abdominal Aortic Aneurysms

Weng

Lou

Bao

et al. 2021

Preprint

View full text Add to dashboard Cite

Aim: The mechanism of abdominal aortic aneurysm (AAA) has not been fully elucidated. In this study, we aimed to map the cellular heterogeneity, molecular alteration, and functional transformation of angiotensin (Ang) II-induced AAA in mice based on single-cell RNA sequencing (sc-RNA seq) technology.Method: Single-cell RNA sequencing was performed on suprarenal abdominal aorta from male APOE-/- C57BL/6 mice of Ang II-induced AAA and shame models. Immunohistochemistry was used to determine the pathophysiological characteristics of AAA, and sc-RNA seq was used to determine the heterogeneity and phenotypic transformation of all cell types. A single-cell trajectory was performed to predict the differentiation of fibroblasts. Finally ligand–receptor analysis was used to evaluate intercellular communication between fibroblasts and smooth muscle cells.Results: More than 27,000 cells were isolated and 25 clusters representing 8 types of cells were identified, including fibroblasts, macrophages, endothelial cells, smooth muscle cells, T lymphocytes, B lymphocytes, granulocytes, and natural killer cells. During AAA progression, the function and phenotype of different type cells altered separately. The pro-inflammatory function of inflammatory cells was enhanced. The proliferation phenotype degreased while pro-inflammatory, regeneration and damage-related phenotypes increased in endothelial cells. Smooth muscle cells also transformed from contractile to secretory phenotype. The alterations of fibroblasts were the most conspicuous according sub-group clustering analysis. Single-cell trajectory revealed the critical reprogramming genes of fibroblasts mainly enriched in regulation of immune system. Finally, the ligand–receptor analysis confirmed that increases in secondary collagen synthesis led by fibroblasts were one of the most prominent characteristics of Ang II-induced AAA.Conclusion: Our study revealed the cellular heterogeneity of Ang II-induced AAA. Fibroblasts may play a central role in Ang II-induced AAA progression according multiple biological functions including immune regulation and extracellular matrix metabolic balance. Our study may provide us with a different perspective on the etiology and pathogenesis of AAA.

show abstract

Section: Discussionmentioning

confidence: 99%

Single-cell RNA Sequencing Technology Revealed the Pivotal Role of Fibroblast Heterogeneity in Ang II-Induced Abdominal Aortic Aneurysms

Weng

Lou

Bao

et al. 2021

Preprint

View full text Add to dashboard Cite

show abstract

“…COMP is identified as an endogenous allosteric deviation modulator of angiotensin II type 1 (AT1) receptor. COMP deficiency activates the AT1 receptor/β-arrestin-2 signal ( Figure 6 ), which exacerbates the activation of AT1 receptor-related diseases, such as abdominal aortic aneurysm [ 27 ]. Aortic aneurysm in COMP −/− mice could be rescued by the application of a peptidomimetic that mimics the AT1-binding motif of COMP [ 27 ].…”

Section: Comp and Cardiovascular Diseasementioning

confidence: 99%

“…COMP deficiency activates the AT1 receptor/β-arrestin-2 signal ( Figure 6 ), which exacerbates the activation of AT1 receptor-related diseases, such as abdominal aortic aneurysm [ 27 ]. Aortic aneurysm in COMP −/− mice could be rescued by the application of a peptidomimetic that mimics the AT1-binding motif of COMP [ 27 ]. Human studies also show that COMP downregulation is associated with aortic aneurysm [ 114 ].…”

Section: Comp and Cardiovascular Diseasementioning

confidence: 99%

“…Due to the protective effects of COMP on cartilage, a thorough understanding of COMP functions and the related signaling pathways is beneficial for novel therapeutic strategies for cartilage degradation diseases. Recent exciting achievements have implied that COMP is an important gene contributing to other diseases, such as cancer/malignancy [ 22 , 23 , 24 ], cardiovascular diseases [ 25 , 26 , 27 ], and fibrosis [ 28 , 29 , 30 ]. These findings renewed our understanding of COMP functions and ECM biology beyond skeleton.…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Cartilage Oligomeric Matrix Protein, Diseases, and Therapeutic Opportunities

Cui

Zhang

2022

IJMS

View full text Add to dashboard Cite

Cartilage oligomeric matrix protein (COMP) is an extracellular matrix (ECM) glycoprotein that is critical for collagen assembly and ECM stability. Mutations of COMP cause endoplasmic reticulum stress and chondrocyte apoptosis, resulting in rare skeleton diseases. The bouquet-like structure of COMP allows it to act as a bridging molecule that regulates cellular phenotype and function. COMP is able to interact with many other ECM components and binds directly to a variety of cellular receptors and growth factors. The roles of COMP in other skeleton diseases, such as osteoarthritis, have been implied. As a well-established biochemical marker, COMP indicates cartilage turnover associated with destruction. Recent exciting achievements indicate its involvement in other diseases, such as malignancy, cardiovascular diseases, and tissue fibrosis. Here, we review the basic concepts of COMP and summarize its novel functions in the regulation of signaling events. These findings renew our understanding that COMP has a notable function in cell behavior and disease progression as a signaling regulator. Interestingly, COMP shows distinct functions in different diseases. Targeting COMP in malignancy may withdraw its beneficial effects on the vascular system and induce or aggravate cardiovascular diseases. COMP supplementation is a promising treatment for OA and aortic aneurysms while it may induce tissue fibrosis or cancer metastasis.

show abstract

“…Although compelling evidence indicates that biased activation of G protein-coupled receptor (GPCR) signalling, like AT 1 R signalling, plays a role in vascular homeostasis and injury, it is unclear whether clinically relevant endogenous-biased antagonism of AT 1 R signalling exists in physiological and pathophysiological circumstances. Explorations of the endogenous-biased antagonism of AT 1 R or other GPCRs may provide innovative treatment options for cardiovascular disorders [ 64 ].…”

Section: The Renal View Of Conventional Ras In Aki Induced By Ririmentioning

confidence: 99%

View of the Renin-Angiotensin System in Acute Kidney Injury Induced by Renal Ischemia-Reperfusion Injury

Karimi¹,

Maleki

Nematbakhsh

2022

J Renin Angiotensin Aldosterone Syst

View full text Add to dashboard Cite

Renal ischemia-reperfusion injury (RIRI) is a sequence of complicated events that is defined as a reduction of the blood supply followed by reperfusion. RIRI is the leading cause of acute kidney injury (AKI). Among the diverse mediators that take part in RIRI-induced AKI, the renin-angiotensin system (RAS) plays an important role via conventional (angiotensinogen, renin, angiotensin-converting enzyme (ACE), angiotensin (Ang) II, and Ang II type 1 receptor (AT1R)) and nonconventional (ACE2, Ang 1-7, Ang 1-9, AT2 receptor (AT2R), and Mas receptor (MasR)) axes. RIRI alters the balance of both axes so that RAS can affect RIRI-induced AKI. In overall, the alteration of Ang II/AT1R and AKI by RIRI is important to consider. This review has looked for the effects and interactions of RAS activities during RIRI conditions.

show abstract

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

Cited by 34 publications

References 82 publications

Single-cell RNA Sequencing Technology Revealed the Pivotal Role of Fibroblast Heterogeneity in Ang II-Induced Abdominal Aortic Aneurysms

Single-cell RNA Sequencing Technology Revealed the Pivotal Role of Fibroblast Heterogeneity in Ang II-Induced Abdominal Aortic Aneurysms

Cartilage Oligomeric Matrix Protein, Diseases, and Therapeutic Opportunities

View of the Renin-Angiotensin System in Acute Kidney Injury Induced by Renal Ischemia-Reperfusion Injury

Contact Info

Product

Resources

About