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Article: C5a-C5aR1 induces endoplasmic reticulum stress to accelerate vascular calcification via PERK-eIF2α-ATF4-CREB3L1 pathway

TitleC5a-C5aR1 induces endoplasmic reticulum stress to accelerate vascular calcification via PERK-eIF2α-ATF4-CREB3L1 pathway
Authors
KeywordsC5a-C5aR1
CREB3L1
Endoplasmic reticulum stress
PERK-eIF2α-ATF4 pathway
Vascular calcification
Issue Date25-Nov-2023
PublisherOxford University Press
Citation
Cardiovascular Research, 2023, v. 119, n. 15, p. 2563-2578 How to Cite?
Abstract

Aims

Vascular calcification (VC) predicts the morbidity and mortality in cardiovascular diseases. Vascular smooth muscle cells (VSMCs) osteogenic transdifferentiation is the crucial pathological basis for VC. To date, the molecular pathogenesis is still largely unclear. Notably, C5a-C5aR1 contributes to the development of cardiovascular diseases, and its closely related to physiological bone mineralization which is similar to VSMCs osteogenic transdifferentiation. However, the role and underlying mechanisms of C5a-C5aR1 in VC remain unexplored.

Methods and results

A cross-sectional clinical study was utilized to examine the association between C5a and VC. Chronic kidney diseases mice and calcifying VSMCs models were established to investigate the effect of C5a-C5aR1 in VC, evaluated by changes in calcium deposition and osteogenic markers. The cross-sectional study identified that high level of C5a was associated with increased risk of VC. C5a dose-responsively accelerated VSMCs osteogenic transdifferentiation accompanying with increased the expression of C5aR1. Meanwhile, the antagonists of C5aR1, PMX 53, reduced calcium deposition, and osteogenic transdifferentiation both in vivo and in vitro. Mechanistically, C5a-C5aR1 induced endoplasmic reticulum (ER) stress and then activated PERK-eIF2α-ATF4 pathway to accelerated VSMCs osteogenic transdifferentiation. In addition, cAMP-response element-binding protein 3-like 1 (CREB3L1) was a key downstream mediator of PERK-eIF2α-ATF4 pathway which accelerated VSMCs osteogenic transdifferentiation by promoting the expression of COL1α1.

Conclusions

High level of C5a was associated with increased risk of VC, and it accelerated VC by activating the receptor C5aR1. PERK-eIF2α-ATF4-CREB3L1 pathway of ER stress was activated by C5a-C5aR1, hence promoting VSMCs osteogenic transdifferentiation. Targeting C5 or C5aR1 may be an appealing therapeutic target for VC.


Persistent Identifierhttp://hdl.handle.net/10722/339706
ISSN
2023 Impact Factor: 10.2
2023 SCImago Journal Rankings: 2.809
ISI Accession Number ID

 

DC FieldValueLanguage
dc.contributor.authorLiu, A-
dc.contributor.authorChen, Z-
dc.contributor.authorLi, X-
dc.contributor.authorXie, C-
dc.contributor.authorChen, Y-
dc.contributor.authorSu, X-
dc.contributor.authorChen, Y-
dc.contributor.authorZhang, M-
dc.contributor.authorChen, J-
dc.contributor.authorYang, T-
dc.contributor.authorShen, J-
dc.contributor.authorHuang, H -
dc.date.accessioned2024-03-11T10:38:44Z-
dc.date.available2024-03-11T10:38:44Z-
dc.date.issued2023-11-25-
dc.identifier.citationCardiovascular Research, 2023, v. 119, n. 15, p. 2563-2578-
dc.identifier.issn0008-6363-
dc.identifier.urihttp://hdl.handle.net/10722/339706-
dc.description.abstract<p>Aims</p><p>Vascular calcification (VC) predicts the morbidity and mortality in cardiovascular diseases. Vascular smooth muscle cells (VSMCs) osteogenic transdifferentiation is the crucial pathological basis for VC. To date, the molecular pathogenesis is still largely unclear. Notably, C5a-C5aR1 contributes to the development of cardiovascular diseases, and its closely related to physiological bone mineralization which is similar to VSMCs osteogenic transdifferentiation. However, the role and underlying mechanisms of C5a-C5aR1 in VC remain unexplored.</p><p>Methods and results</p><p>A cross-sectional clinical study was utilized to examine the association between C5a and VC. Chronic kidney diseases mice and calcifying VSMCs models were established to investigate the effect of C5a-C5aR1 in VC, evaluated by changes in calcium deposition and osteogenic markers. The cross-sectional study identified that high level of C5a was associated with increased risk of VC. C5a dose-responsively accelerated VSMCs osteogenic transdifferentiation accompanying with increased the expression of C5aR1. Meanwhile, the antagonists of C5aR1, PMX 53, reduced calcium deposition, and osteogenic transdifferentiation both <em>in vivo</em> and <em>in vitro</em>. Mechanistically, C5a-C5aR1 induced endoplasmic reticulum (ER) stress and then activated PERK-eIF2α-ATF4 pathway to accelerated VSMCs osteogenic transdifferentiation. In addition, cAMP-response element-binding protein 3-like 1 (CREB3L1) was a key downstream mediator of PERK-eIF2α-ATF4 pathway which accelerated VSMCs osteogenic transdifferentiation by promoting the expression of COL1α1.</p><p>Conclusions</p><p>High level of C5a was associated with increased risk of VC, and it accelerated VC by activating the receptor C5aR1. PERK-eIF2α-ATF4-CREB3L1 pathway of ER stress was activated by C5a-C5aR1, hence promoting VSMCs osteogenic transdifferentiation. Targeting C5 or C5aR1 may be an appealing therapeutic target for VC.</p>-
dc.languageeng-
dc.publisherOxford University Press-
dc.relation.ispartofCardiovascular Research-
dc.subjectC5a-C5aR1-
dc.subjectCREB3L1-
dc.subjectEndoplasmic reticulum stress-
dc.subjectPERK-eIF2α-ATF4 pathway-
dc.subjectVascular calcification-
dc.titleC5a-C5aR1 induces endoplasmic reticulum stress to accelerate vascular calcification via PERK-eIF2α-ATF4-CREB3L1 pathway-
dc.typeArticle-
dc.identifier.doi10.1093/cvr/cvad133-
dc.identifier.scopuseid_2-s2.0-85176235197-
dc.identifier.volume119-
dc.identifier.issue15-
dc.identifier.spage2563-
dc.identifier.epage2578-
dc.identifier.eissn1755-3245-
dc.identifier.isiWOS:001187618900001-
dc.identifier.issnl0008-6363-

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