The calcium‐sensing receptor alleviates endothelial inflammation in atherosclerosis through regulation of integrin β1‐NLRP3 inflammasome

Abstract

Atherosclerosis (AS) is a chronic inflammatory disease of arteries. Endothelial inflammation is key to the initiation and development of AS. The calcium‐sensing receptor (CaSR) is expressed in endothelial cells (ECs) but its role in endothelial inflammation during AS remains unclear. This study focused on the involvement of CaSR in regulating endothelial inflammation and its underlying mechanisms, providing novel insights for AS therapy. Here, we observed that CaSR agonist NPS‐R568 significantly reduced atherosclerotic lesions and aortic inflammation in high‐fat diet (HFD)‐fed ApoE−/− mice, while enhancing the expression of CaSR in aortic tissues. In vitro, human umbilical vein endothelial cells (HUVECs) exposed to oxidized low‐density lipoprotein (oxLDL) at 20 μg·mL−1 triggered inflammation, as indicated by the upregulation of vascular cell adhesion molecule‐1 (VCAM‐1), interleukin (IL)‐6, and IL‐1β expression, along with increased adherence of THP‐1 or U937 cells to the HUVECs. Additionally, treatment with 20 μg·mL−1 oxLDL led to downregulation of CaSR expression in HUVECs. The administration of CaSR agonist NPS‐R568 or overexpression of CaSR in HUVECs resulted in a significant reversal of inflammation induced by oxLDL. Mechanistically, CaSR was found to mitigate NLRP3 inflammasome activation by downregulating the protein level of integrin β1. In conclusion, our study elucidates the beneficial role of CaSR in reducing endothelial inflammation in AS through the regulation of integrin β1 and the subsequent NLRP3 inflammasome. CaSR emerges as a promising target for potential therapeutic interventions in AS.