Abstract
Emerging evidence indicates the pronounced role of inflammasome activation linked to reactive oxygen species (ROS) in the sterile inflammatory response triggered by ischemia/reperfusion (I/R) injury. Ethyl pyruvate (EP) is an antioxidant and conveys myocardial protection against I/R injury, while the exact mechanisms remain elusive. We aimed to investigate the effect of EP on myocardial I/R injury through mechanisms related to ROS and inflammasome regulation. The rats were randomly assigned to four groups: (1) sham, (2) I/R-control (IRC), (3) EP-pretreatment + I/R, and (4) I/R + EP-posttreatment. I/R was induced by a 30 min ligation of the left anterior descending artery followed by 4 h of reperfusion. EP (50 mg/kg) was administered intraperitoneally at 1 h before ischemia (pretreatment) or upon reperfusion (posttreatment). Both pre- and post-EP treatment resulted in significant reductions in myocardial infarct size (by 34% and 31%, respectively) and neutrophil infiltration. I/R-induced myocardial expressions of NADPH oxidase-4, carnitine palmitoyltransferase 1A, and thioredoxin-interacting protein (TXNIP) were mitigated by EP. EP treatment was associated with diminished inflammasome activation (NOD-like receptor 3 (NLRP3), apoptosis-associated speck-like protein, and caspase-1) and interleukin-1β induced by I/R. I/R-induced phosphorylation of ERK and p38 were also mitigated with EP treatments. In H9c2 cells, hypoxia-induced TXNIP and NLRP3 expressions were inhibited by EP and to a lesser degree by U0126 (MEK inhibitor) and SB203580 (p38 inhibitor) as well. EP's downstream protective mechanisms in myocardial I/R injury would include mitigation of ROS-mediated NLRP3 inflammasome upregulation and its associated pathways, partly via inhibition of hypoxia-induced phosphorylation of ERK and p38.
Highlights
Restoration of coronary flow is essential for myocardial salvage and remains the cornerstone of therapies for myocardial infarction
mean arterial pressure (MAP) recorded during ischemia were significantly lower compared to their corresponding baseline values in all groups, while Heart rate (HR) did not show any significant changes throughout the study period
NLRP3 expression was similar between the EPpre group and the sham group, while it was significantly increased in the EPpost group compared with the sham group (Figure 2)
Summary
Restoration of coronary flow is essential for myocardial salvage and remains the cornerstone of therapies for myocardial infarction. Reperfusion inevitably accompanies a specific, sterile inflammation that has been extensively studied to be the principal cause of further myocardial damage and dysfunction [1]. In that context, emerging evidence indicates the role of inflammasome as one of the key regulators of this inflammation-mediated ischemia/reperfusion (I/R) injury [2]. As an integral component of the inherent immune system, activation of the inflammasome results in the production of potent inflammatory cytokines, interleukin- (IL-) 1β and IL-18, that promote further myocardial damage after I/R [4, 5]. Accounting for its dominant role in mediating inflammation, Oxidative Medicine and Cellular Longevity experimental endeavors to find therapies targeting the inflammasome in neurodegenerative or metabolic disorders have been made with some promising results [6]. Evidence regarding relevant therapies in myocardial I/R injury is scarce
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