Calcium-Sensing Receptor-NLRP3 Inflammasome Signaling in Cardiovascular Diseases: Preclinical Evidence and Translational Perspectives.

Abstract

The chronic low-grade inflammation driven by NLR family pyrin domain containing 3 (NLRP3) inflammasome is increasingly acknowledged as an underlying mechanism of myocardial infarction, heart failure, atrial fibrillation, hypertension, and atherosclerosis. Extracellular Ca2+, amino acids, and other ligands link to intracellular Ca2+ overload, mitochondrial dysfunction, reactive oxygen species generation, thioredoxin-interacting protein activation, and NF-κB-dependent inflammasome priming via the calcium-sensing receptor (CaSR). Experimental studies indicate that CaSR may activate the NLRP3 inflammasome through these pathways in a cell- and context-dependent manner. In preclinical cardiovascular models, CaSR-mediated NLRP3 signaling has been implicated in neutrophil- and macrophage-mediated post-MI remodeling, atrial cardiomyocyte inflammatory remodeling in atrial fibrillation, and vascular smooth muscle and endothelial dysfunction in hypertension and atherosclerosis. Importantly, CaSR signalling may exert pro-inflammatory or protective effects depending on the cell type, ligand, dose, disease stage, and local microenvironment. Here, we review preclinical evidence and emerging translational evidence separately, highlighting the CaSR-NLRP3 signalling in cardiovascular disease, describe pharmacologic approaches that may modulate CaSR, NLRP3, or downstream inflammatory pathways, and identify key mechanistic and clinical knowledge gaps. Although direct clinical evidence for a complete CaSR-NLRP3 axis in cardiovascular diseases remains limited, these findings support further investigation of context-specific CaSR-NLRP3 crosstalk as a potential therapeutic target.