Ethyl pyruvate attenuates myocardial ischemia-reperfusion injury exacerbated by hyperglycemia via retained inhibitory effect on HMGB1

Int J Cardiol. 2018 Feb 1;252:156-162. doi: 10.1016/j.ijcard.2017.11.038. Epub 2017 Nov 21.

Abstract

Background: Hyperglycemia (HG) exacerbates myocardial ischemia/reperfusion (I/R) injury and renders protective strategies ineffective by amplified inflammatory response via enhanced high-mobility group box-1 (HMGB1) release. This study investigated the role of ethyl pyruvate (EP) against myocardial I/R injury under a clinically relevant HG condition.

Methods: Sprague-Dawley rats (n=76) were randomly assigned to 6 groups: normoglycemia (NG)-Sham, NG-I/R-control (C, saline), NG-I/R-EP treatment (50mg/kg) upon reperfusion, HG-Sham, HG-I/R-C, and HG-I/R-EP treatment upon reperfusion. HG was induced by 1.2g/kg dextrose. I/R was induced by ligation of the left anterior descending artery for 30min followed by 4h of reperfusion.

Results: HG resulted in exacerbation of myocardial infarct size by 19% with amplified activation of HMGB1-receptors of advanced glycation end products/toll like receptors-NF-κB pathway compared to NG following I/R, which all could be attenuated by EP. EP treatment was associated with diminished tumor necrosis factor-α, interleukin-1β, and interleukin-6 expressions. It also served to normalize the increase in pro-apoptotic Bax and the decrease in anti-apoptotic Bcl-2 protein levels. These effects were associated with decreased myocardial apoptosis and infarct size (by 30% and 36% in the NG and HG groups, respectively) regardless of the glycemic condition.

Conclusion: HG exacerbated myocardial I/R injury through amplified inflammatory response via increased HMGB1 level. EP treatment upon reperfusion conveyed significant myocardial protection against the I/R injury under both NG and HG conditions. Common to both glycemic conditions, associated mechanisms involved attenuated increase in HMGB1 level and suppression of its down-stream pathways.

Keywords: Ethyl pyruvate; HMGB1 protein; Hyperglycemia; Myocardial reperfusion injury.

MeSH terms

  • Animals
  • HMGB1 Protein / antagonists & inhibitors*
  • HMGB1 Protein / blood*
  • Hyperglycemia / blood*
  • Hyperglycemia / complications
  • Myocardial Reperfusion Injury / blood*
  • Myocardial Reperfusion Injury / drug therapy*
  • Myocardial Reperfusion Injury / etiology
  • Pyruvates / pharmacology
  • Pyruvates / therapeutic use*
  • Random Allocation
  • Rats
  • Rats, Sprague-Dawley

Substances

  • HMGB1 Protein
  • Hbp1 protein, rat
  • Pyruvates
  • ethyl pyruvate