Calcium-sensing receptor on neutrophil promotes myocardial apoptosis and fibrosis after acute myocardial infarction via NLRP3 inflammasome activation

Abstract Background The infiltration of neutrophils aggravates inflammatory response in acute myocardial infarction (AMI), and the role of calcium-sensing receptor (CaSR) in neutrophil-associated inflammation is largely unknown. The aim of this study was to evaluate the regulatory effects of CaSR on NLRP3 inflammasome in neutrophils and to explore its role in AMI-related ventricular remodeling. Methods The expression of CaSR, NLPR3 inflammasome and IL-1β in peripheral blood and infiltrated neutrophils in AMI patients and rats was detected by western blotting and immunofluorescence. Cardiomyocytes apoptosis was detected by western blotting and transmission electron microscopy. The degree of fibrosis was evaluated by Masson staining and western blotting. Results We found upregulation of CaSR, NLRP3 inflammasome, Caspase-1 and IL-1β in peripheral neutrophils from AMI patients compared with matched healthy controls, peaking on day 1 and decreasing gradually till 7 d. Peripheral and infiltrating neutrophils from AMI rats showed the same trend. Calindol enhanced NLRP3 inflammasome activation and IL-1β release in neutrophils from healthy volunteers; which was blocked by inhibitors of PLC-IP3 pathway and ER-Ca2+ release. Calhex-231 decreased NLRP3 inflammasome activation and IL-1β release in neutrophils from AMI patients. The calindol-stimulated neutrophils from healthy volunteers promoted cardiomyocytes apoptosis and fibrosis of cardiac fibroblasts from healthy rats, which were inhibited by calhex-231. Conclusion The results suggest that CaSR activates NLRP3 inflammasome in neutrophils, contributing to ventricular remodeling after AMI. CaSR inhibition may be a potential therapeutic target for heart failure in AMI.