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

Autor:	Liu A; Department of Cardiology, Joint Laboratory of Guangdong-Hong Kong-Macao Universities for Nutritional Metabolism and Precise Prevention and Control of Major Chronic Diseases, The Eighth Affiliated Hospital of Sun Yat-sen University, Shennan Middle Rd, Shenzhen, 518000, China., Chen Z; Department of Nephrology, The Eighth Affiliated Hospital of Sun Yat-sen University, Shenzhen, 518000, China., Li X; Department of Cardiology, Joint Laboratory of Guangdong-Hong Kong-Macao Universities for Nutritional Metabolism and Precise Prevention and Control of Major Chronic Diseases, The Eighth Affiliated Hospital of Sun Yat-sen University, Shennan Middle Rd, Shenzhen, 518000, China., Xie C; Department of Cardiology, Joint Laboratory of Guangdong-Hong Kong-Macao Universities for Nutritional Metabolism and Precise Prevention and Control of Major Chronic Diseases, The Eighth Affiliated Hospital of Sun Yat-sen University, Shennan Middle Rd, Shenzhen, 518000, China., Chen Y; Department of Cardiology, Joint Laboratory of Guangdong-Hong Kong-Macao Universities for Nutritional Metabolism and Precise Prevention and Control of Major Chronic Diseases, The Eighth Affiliated Hospital of Sun Yat-sen University, Shennan Middle Rd, Shenzhen, 518000, China., Su X; Department of Nephropathy, Tungwah Hospital of Sun Yat-Sen University, Dongguan, 523000, China., Chen Y; Department of Nephropathy, Tungwah Hospital of Sun Yat-Sen University, Dongguan, 523000, China., Zhang M; Department of Nephropathy, Tungwah Hospital of Sun Yat-Sen University, Dongguan, 523000, China., Chen J; Department of Radiotherapy, Sun Yat-sen Memorial Hospital of Sun Yat-sen University, Guangzhou, 510000, China., Yang T; Department of Nephrology, The Eighth Affiliated Hospital of Sun Yat-sen University, Shenzhen, 518000, China., Shen J; School of Chinese Medicine, Li Ka Shing Faculty of Medicine, State Key Laboratory of Pharmaceutical Biotechnology, The University of Hong Kong, Hong Kong, 999077, China., Huang H; Department of Cardiology, Joint Laboratory of Guangdong-Hong Kong-Macao Universities for Nutritional Metabolism and Precise Prevention and Control of Major Chronic Diseases, The Eighth Affiliated Hospital of Sun Yat-sen University, Shennan Middle Rd, Shenzhen, 518000, China.
Jazyk:	angličtina
Zdroj:	Cardiovascular research [Cardiovasc Res] 2023 Nov 25; Vol. 119 (15), pp. 2563-2578.
DOI:	10.1093/cvr/cvad133
Abstrakt:	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. Competing Interests: Conflict of interest: None declared. (© The Author(s) 2023. Published by Oxford University Press on behalf of the European Society of Cardiology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)
Databáze:	MEDLINE
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