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

by Selleckchem | Dec 30 2023

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 it's 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 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 endoplasmic reticulum stress was activated by C5a-C5aR1, hence promoting VSMCs osteogenic transdifferentiation. Targeting C5 or C5aR1 may be an appealing therapeutic target for VC.

Comments:

The study you've outlined investigates the role of C5a-C5aR1 in vascular calcification (VC), a predictor of morbidity and mortality in cardiovascular diseases. Here's a breakdown of the key points and findings:

### Background:
- **Vascular calcification (VC)** is linked to cardiovascular diseases, and the transdifferentiation of **vascular smooth muscle cells (VSMCs)** into an osteogenic phenotype is a crucial factor in VC development.
- C5a-C5aR1 has been associated with cardiovascular diseases and physiological bone mineralization, resembling VSMC osteogenic transdifferentiation.

### Methodology & Results:
- **Clinical study**: Revealed an association between high C5a levels and an increased risk of VC.
- **Experimental models** (chronic kidney disease mice and calcifying VSMCs): Showed that C5a accelerated VSMC osteogenic transdifferentiation in a dose-dependent manner through increased expression of C5aR1.
- **Intervention**: The C5aR1 antagonist PMX 53 reduced calcium deposition and osteogenic transdifferentiation both in vivo and in vitro.
- **Mechanistic insights**:
- C5a-C5aR1 induced **endoplasmic reticulum stress**, leading to activation of the PERK-eIF2α-ATF4 pathway.
- **CREB3L1** was identified as a downstream mediator of this pathway, promoting VSMC osteogenic transdifferentiation by increasing the expression of COL1α1.

### Conclusion:
- High C5a levels were associated with an increased risk of VC and accelerated VC by activating C5aR1.
- The **PERK-eIF2α-ATF4-CREB3L1** pathway induced by C5a-C5aR1 activation contributed to VSMC osteogenic transdifferentiation.
- Targeting **C5 or C5aR1** could potentially be a promising therapeutic strategy for preventing or treating VC.

### Significance:
- Understanding the molecular mechanisms behind VC, especially the involvement of C5a-C5aR1 and the identified pathways, offers potential avenues for developing targeted therapies to mitigate VC-related cardiovascular risks.

This study's findings emphasize the potential significance of targeting the C5a-C5aR1 axis to intervene in vascular calcification, paving the way for future therapeutic interventions in cardiovascular diseases associated with VC.