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.
Department of Nephrology, The Eighth Affiliated Hospital of Sun Yat-sen University, Shenzhen, 518000, China.
Cardiovasc Res. 2023 Nov 25;119(15):2563-2578. doi: 10.1093/cvr/cvad133.
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.
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.
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.
血管钙化（VC）可预测心血管疾病的发病率和死亡率。血管平滑肌细胞（VSMCs）成骨转化是 VC 的关键病理基础。迄今为止，其分子发病机制在很大程度上仍不清楚。值得注意的是，C5a-C5aR1 有助于心血管疾病的发展，其与生理骨矿化密切相关，而生理骨矿化类似于 VSMCs 的成骨转化。然而，C5a-C5aR1 在 VC 中的作用及其潜在机制仍未被探索。
利用横断面临床研究来检验 C5a 与 VC 之间的关系。建立慢性肾脏病小鼠和钙化 VSMCs 模型，通过钙沉积和成骨标志物的变化来评估 C5a-C5aR1 在 VC 中的作用。该横断面研究表明，高水平的 C5a 与 VC 风险增加相关。C5a 呈剂量依赖性加速 VSMCs 成骨转化，同时增加 C5aR1 的表达。同时，C5aR1 的拮抗剂 PMX53 减少了体内和体外的钙沉积和成骨转化。在机制上，C5a-C5aR1 诱导内质网（ER）应激，然后激活 PERK-eIF2α-ATF4 通路，加速 VSMCs 成骨转化。此外，cAMP 反应元件结合蛋白 3 样 1（CREB3L1）是 PERK-eIF2α-ATF4 通路的关键下游介质，通过促进 COL1α1 的表达，加速 VSMCs 成骨转化。
高水平的 C5a 与 VC 风险增加相关，它通过激活受体 C5aR1 加速 VC。C5a-C5aR1 激活内质网应激的 PERK-eIF2α-ATF4 通路，从而促进 VSMCs 成骨转化。针对 C5 或 C5aR1 可能是 VC 的一种有吸引力的治疗靶点。
