Role of NLRP3 Inflammasome in Myocardial Ischemia-Reperfusion Injury and Ventricular Remodeling

Abstract

Reperfusion therapy is the optimal therapy for acute myocardial infarction (AMI), but acute inflammatory injury and chronic heart failure (HF) after myocardial ischemia and reperfusion (MI/R) remain the leading cause of death after AMI. Pyroptosis, a newly discovered form of cell death, has been proven to play a significant role in the acute reperfusion process and the subsequent chronic process of ventricular remodeling. Current research shows that multiple stimuli activate the pyroptotic signaling pathway and contribute to cell death and nonbacterial inflammation after MI/R. These stimuli promote the assembly of the nucleotide-binding and oligomerization-like receptor pyrin domain-containing protein 3 (NLRP3) inflammasome by activating NLRP3. The mature NLRP3 inflammasome cleaves procaspase-1 to active caspase-1, which leads to mature processing of interleukin (IL)-18, IL-1ß, and gasdermin D (GSDMD) protein. That eventually results in cell lysis and generation of nonbacterial inflammation. The present review summarizes the mechanism of NLRP3 inflammasome activation after MI/R and discusses the role that NLRP3-mediated pyroptosis plays in the pathophysiology of MI/R injury and ventricular remodeling. We also discuss potential mechanisms and targeted therapy for which there is evidence supporting treatment of ischemic heart disease.

Figure 1

A dual-signal model mediated the activation process of the nucleotide-binding and oligomerization-like receptor pyrin domain-containing protein 3 (NLRP3) inflammasome. The first step was stimulating promotion of nuclear factor-κB into the nucleus to regulate the transcription and translation of the NLRP gene in the nucleus and release it into the cytoplasm. The second step was divided into the non-canonical caspase-11-mediated and canonical NLRP3 inflammasome-mediated pyroptosis pathways. Adobe Illustrator CC 2019 (Adobe Software, San Jose, California, United States) was used for drawing.

Figure 2

Potential sources and consequences of nucleotide-binding and oligomerization-like receptor pyrin domain-containing protein 3 (NLRP3) activation signaling pathway during myocardial ischemia and reperfusion (MI/R). MI/R promotes potassium efflux, which directly increases the expression of NIMA-related kinase 7 (NEK7) to form the NLRP3 complex. MI/R promotes sodium-hydron exchange and sodium-calcium exchange and sarcoplasmic reticulum and endoplasmic reticulum release calcium. Calcium overload causes mitochondrial instability and NLRP3 inflammasome activation. MI/R promotes mitochondrial dysfunction and reactive oxygen species (ROS) production. ROS activates the NLRP3 inflammasomes by regulating nuclear factor-κB, caspase-11, and thioredoxin-interacting protein. Adobe Illustrator CC 2019 (Adobe Software, San Jose, California, United States) was used for drawing.