Abstract
The reactive oxygen species- (ROS-) induced nod-like receptor protein-3 (NLRP3) inflammasome triggers sterile inflammatory responses and pyroptosis, which is a proinflammatory form of programmed cell death initiated by the activation of inflammatory caspases. NLRP3 inflammasome activation plays an important role in myocardial ischemia/reperfusion (MI/R) injury. Our present study investigated whether diabetes aggravated MI/R injury through NLRP3 inflammasome-mediated pyroptosis. Type 1 diabetic rat model was established by intraperitoneal injection of streptozotocin (60 mg/kg). MI/R was induced by ligating the left anterior descending artery (LAD) for 30 minutes followed by 2 h reperfusion. H9C2 cardiomyocytes were exposed to high glucose (HG, 30 mM) conditions and hypoxia/reoxygenation (H/R) stimulation. The myocardial infarct size, CK-MB, and LDH release in the diabetic rats subjected to MI/R were significantly higher than those in the nondiabetic rats, accompanied with increased NLRP3 inflammasome activation and increased pyroptosis. Inhibition of inflammasome activation with BAY11-7082 significantly decreased the MI/R injury. In vitro studies showed similar effects, as BAY11-7082 or the ROS scavenger N-acetylcysteine, attenuated HG and H/R-induced H9C2 cell injury. In conclusion, hyperglycaemia-induced NLRP3 inflammasome activation may be a ROS-dependent process in pyroptotic cell death, and NLRP3 inflammasome-induced pyroptosis aggravates MI/R injury in diabetic rats.
Highlights
Acute myocardial infarction (AMI) remains a major cause of morbidity and mortality among diabetic patients [1]
The results demonstrated that high glucose (HG) conditions could significantly increase the expression of nod-like receptor (NLR) protein3 (NLRP3) (Figure 5(a)), associated speck-like protein (ASC) (Figure 5(b)), procaspase-1 and caspase-1 (Figure 5(c)), and IL-1β (Figure 5(d)), and these alterations were further increased by H/R stimulation
Caspase-1 (Figure 7(c)) and mature IL-1β (Figure 7(d)) expressions were significantly downregulated in the NAC inhibitor-treated groups. These results showed that the reactive oxygen species (ROS) scavenger NAC can alleviate H/R-induced cell injury by decreasing NLRP3 inflammasome activation, reducing activated caspase-1-induced pyroptotic cell death and IL-1β levels in both low glucose (LG) and HG conditions
Summary
Acute myocardial infarction (AMI) remains a major cause of morbidity and mortality among diabetic patients [1]. Increasing evidence has shown that diabetes increases the sensitivity to myocardial ischemia/reperfusion (MI/R), and following AMI, diabetic patients had a larger infarct size and a higher new congestive heart failure rate than nondiabetic patients [3]. This may be due to diabetes-mediated metabolic disorders, including hyperglycaemia, insulin resistance, and dyslipidaemia [4]. A variety of structurally dissimilar agonists, including pathogens, extracellular ATP, urate crystallisation, virus-associated DNA, RNA, poreforming toxins, and DAMPs (K+ efflux, lysosomal destabilization, and mitochondrial ROS), can activate the NLRP3 inflammasome to mediate downstream inflammatory responses [18, 19]
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