Ziqi Ren1, Kelaier Yang2, Meng Zhao3, Wenxiu Liu3, Xin Zhang3, Jinyu Chi3, Zhiyu Shi3, Xiaohui Zhang3, Yu Fu3, Yue Liu3, Xinhua Yin4. 1. Department of Cardiology, First Affiliated Hospital of Harbin Medical University, Harbin, China; Department of Hyperbaric Oxygen, Beijing Tiantan Hospital, Capital Medical University, Beijing, China. 2. Department of Endocrinology, First Affiliated Hospital of Harbin Medical University, Harbin, China. 3. Department of Cardiology, First Affiliated Hospital of Harbin Medical University, Harbin, China. 4. Department of Cardiology, First Affiliated Hospital of Harbin Medical University, Harbin, China. Electronic address: yinxinhua5063@163.com.
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 nucleotide-binding oligomerization domain-like receptor pyrin domain-containing 3 (NLRP3) inflammasome in neutrophils and to explore its role in AMI-related ventricular remodelling. METHODS: The expression of CaSR, NLRP3 inflammasome, and interleukin 1β (IL-1β) in peripheral blood and infiltrating neutrophils in patients and rats with AMI was detected by western blotting and immunofluorescence. Cardiomyocyte 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 patients with AMI compared with matched healthy controls, peaking on day 1 and decreasing gradually till 7 days. Peripheral and infiltrating neutrophils from rats with AMI showed the same trend. Calindol enhanced NLRP3 inflammasome activation and IL-1β release in neutrophils from healthy volunteers, which was blocked by inhibitors of the PLC-IP3 pathway and ER-Ca2+ release. Calhex-231 decreased NLRP3 inflammasome activation and IL-1β release in neutrophils from patients with AMI. The calindol-stimulated neutrophils from healthy rats promoted cardiomyocyte 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 remodelling after AMI. CaSR inhibition may be a potential therapeutic target for heart failure in AMI.
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 nucleotide-binding oligomerization domain-like receptor pyrin domain-containing 3 (NLRP3) inflammasome in neutrophils and to explore its role in AMI-related ventricular remodelling. METHODS: The expression of CaSR, NLRP3 inflammasome, and interleukin 1β (IL-1β) in peripheral blood and infiltrating neutrophils in patients and rats with AMI was detected by western blotting and immunofluorescence. Cardiomyocyte 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 patients with AMI compared with matched healthy controls, peaking on day 1 and decreasing gradually till 7 days. Peripheral and infiltrating neutrophils from rats with AMI showed the same trend. Calindol enhanced NLRP3 inflammasome activation and IL-1β release in neutrophils from healthy volunteers, which was blocked by inhibitors of the PLC-IP3 pathway and ER-Ca2+ release. Calhex-231 decreased NLRP3 inflammasome activation and IL-1β release in neutrophils from patients with AMI. The calindol-stimulated neutrophils from healthy rats promoted cardiomyocyte 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 remodelling after AMI. CaSR inhibition may be a potential therapeutic target for heart failure in AMI.
Authors: Dijana Stojanovic; Valentina Mitic; Miodrag Stojanovic; Jelena Milenkovic; Aleksandra Ignjatovic; Maja Milojkovic Journal: Front Cardiovasc Med Date: 2022-05-31
Authors: Denisa Baci; Annalisa Bosi; Luca Parisi; Giuseppe Buono; Lorenzo Mortara; Giuseppe Ambrosio; Antonino Bruno Journal: Int J Mol Sci Date: 2020-09-28 Impact factor: 5.923