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 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: Ziqi Ren, Kelaier Yang, Meng Zhao, Wenxiu Liu, Xin Zhang, Jinyu Chi, Zhiyu Shi, Xiaohui Zhang, Yu Fu, Yue Liu, Xinhua Yin
• Journal: The Canadian journal of cardiology (Can J Cardiol) Vol. 36 Issue 6 Pg. 893-905 (06 2020) ISSN: 1916-7075 [Electronic] England
• PMID: 32224080 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2019 Canadian Cardiovascular Society. Published by Elsevier Inc. All rights reserved.

Chemical References

• (R)-2-(1-(1-naphthyl)ethyl-aminom-ethyl)indole
• Benzamides
• Cyclohexylamines
• Indoles
• Inflammasomes
• Inflammation Mediators
• Interleukin-1beta
• N(1)-(4-chlorobenzoyl)-N(2)-(1-(1-naphthyl)ethyl)-1,2-diaminocyclohexane
• NLR Family, Pyrin Domain-Containing 3 Protein
• Naphthalenes
• Protective Agents
• Receptors, Calcium-Sensing

Topics

• Animals
• Apoptosis (immunology)
• Benzamides (pharmacology)
• Cyclohexylamines (pharmacology)
• Fibrosis (prevention & control)
• Humans
• Indoles (pharmacology)
• Inflammasomes (metabolism)
• Inflammation Mediators (metabolism)
• Interleukin-1beta (immunology)
• Myocardial Infarction (immunology, metabolism, pathology)
• Myocardium (pathology)
• Myocytes, Cardiac (immunology, metabolism)
• NLR Family, Pyrin Domain-Containing 3 Protein (metabolism)
• Naphthalenes (pharmacology)
• Neutrophils (immunology)
• Protective Agents
• Rats
• Receptors, Calcium-Sensing (antagonists & inhibitors, immunology)
• Ventricular Remodeling (drug effects)