Uric acid aggravates myocardial ischemia-reperfusion injury via ROS/NLRP3 pyroptosis pathway

Biomed Pharmacother. 2021 Jan:133:110990. doi: 10.1016/j.biopha.2020.110990. Epub 2020 Nov 21.

Abstract

Background: The NOD-like receptor pyrin domain-containing protein 3 (NLRP3) inflammasome activation-mediated pyroptosis pathway has been linked to myocardial ischemia-reperfusion (MI/R) injury. This study explored whether uric acid (UA) aggravates MI/R injury through NLRP3 inflammasome-mediated pyroptosis.

Methods: In vivo, a mouse MI/R model was established by ligating the left coronary artery, and a mouse hyperuricemia model was created by intraperitoneal injection of potassium oxonate (PO). Then, the myocardial infarction (MI) size; terminal deoxynucleotidyl transferase dUTP nick end-labeling (TUNEL) immunofluorescence; and serum levels of lactate dehydrogenase (LDH), creatine kinase isoenzyme (CK-MB), and UA, as well as the expression level of pyroptosis-related protein and caspase-3 in heart tissues, were measured. Separately, primary mouse cardiomyocytes were cultured in vitro to create a hypoxia/reoxygenation (H/R) model. We then compared cardiomyocytes viability, TUNEL immunofluorescence, and the levels of LDH, reactive oxygen species (ROS), and pyroptosis-related protein and caspase-3 in cardiomyocytes.

Results: In vivo, the MI area, levels of CK-MB and LDH, rate of cell death, and pyroptosis-related protein and the expression of caspase-3 were significantly higher in the MI/R group than in the sham group, and high UA levels worsened these changes. In vitro, cardiomyocytes viability was significantly downregulated, and the levels of ROS, LDH, pyroptosis-related protein, caspase-3, and the rate of cardiomyocyte death were significantly higher in the H/R + UA group compared with the HR group. Administration of an NLRP3 inflammasome inhibitor and ROS scavenger reversed these effects.

Conclusion: UA aggravates MI/R-induced activation of the NLRP3 inflammatory cascade and pyroptosis by promoting ROS generation, while inflammasome inhibitors and ROS scavengers partly reverse the injury.

Keywords: Myocardial ischemia–reperfusion; NLRP3 inflammasome; Pyroptosis; Reactive oxygen species; Uric acid.

MeSH terms

  • Animals
  • Biomarkers / blood
  • Caspase 3 / metabolism
  • Cell Hypoxia
  • Cells, Cultured
  • Disease Models, Animal
  • Hyperuricemia / blood*
  • Inflammasomes / metabolism*
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Myocardial Infarction / metabolism*
  • Myocardial Infarction / pathology
  • Myocardial Reperfusion Injury / metabolism*
  • Myocardial Reperfusion Injury / pathology
  • Myocytes, Cardiac / metabolism*
  • Myocytes, Cardiac / pathology
  • NLR Family, Pyrin Domain-Containing 3 Protein / metabolism*
  • Pyroptosis*
  • Reactive Oxygen Species / metabolism*
  • Signal Transduction
  • Uric Acid / blood*

Substances

  • Biomarkers
  • Inflammasomes
  • NLR Family, Pyrin Domain-Containing 3 Protein
  • Nlrp3 protein, mouse
  • Reactive Oxygen Species
  • Uric Acid
  • Casp3 protein, mouse
  • Caspase 3