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Ethyl pyruvate retains its protective effect against myocardial ischemia-reperfusion injury under hyperglycemic condition

Other Titles
 고혈당 상태에서 심장 허혈-재관류 손상에 대한 ethyl pyruvate의 심근 보호 효과 
 College of Medicine (의과대학) 
 Dept. of Anesthesiology and Pain Medicine (마취통증의학교실) 
Issue Date
High mobility group box 1 (HMGB1) is one of the key inflammatory mediators known to exert its influence via receptors of advanced glycation end products (RAGE)/toll-like receptors (TLR)–NF-κB signaling pathway in myocardial ischemia/reperfusion (I/R) injury. Also, HMGB1–TLR axis has been shown to play a pathognomonic role in triggering cardiomyocyte apoptosis in myocardial I/R injury. Hyperglycemia, which is common in acute disease state such as acute myocardial infarction or cardiac surgery, is known to aggravate myocardial I/R injury. To complicate matters, hyperglycemia attenuates the protective efficacies of known preventive strategies. Proposed mechanisms include amplification of the HMGB1–RAGE/TLR–NF-κB pathway activation by hyperglycemia. Therefore, under hyperglycemic condition, blockade of the foremost event of this signaling pathway, HMGB1, may ameliorate the myocardial I/R injury. In that context, ethyl pyruvate (EP) could be an efficient protective measure because of its antagonistic effect on HMGB1 release and downstream pathway. This study aimed to investigate the protective role of EP against myocardial I/R injury under a clinically relevant moderate hyperglycemic condition and its associated mechanisms. Sprague-Dawley rats (n = 104) were randomly assigned to eight groups: normoglycemia-Sham (NG-sham, n = 10), normoglycemia-I/R-control-saline (NG-IRC, n = 14), normoglycemia-EP treatment before ischemia (NG-pre-EP, n =14), normoglycemia-EP treatment upon reperfusion (NG-post-EP, n = 14), hyperglycemia-Sham (HG-sham, n = 10), hyperglycemia-I/R-control-saline (HG-IRC, n = 14), hyperglycemia-EP treatment before ischemia (HG-pre-EP, n = 14), and hyperglycemia-EP treatment upon reperfusion (HG-post-EP, n = 14). The rats received 1.2 g/kg dextrose or same volume of normal saline depending on the group before procedure. I/R was induced by a 30 minute-period of left anterior descending coronary artery ligation followed by reperfusion for 4 hours. At one hour before ischemia (pre-EP) or upon reperfusion (post-EP), intravenous 50 mg/kg of EP was administered. Hyperglycemia resulted in exacerbation of myocardial infarct size with amplification of HMGB1–RAGE/TLR–NF-κB pathway activation compared to normoglycemia following I/R. As compared with IRC and pre-EP, post-EP significantly reduced myocardial infarct size and myocardial apoptosis after myocardial I/R under normoglycemia and this protective effect of EP was preserved under hyperglycemic condition. EP treatment upon reperfusion decreased HMGB1 protein level and the expression of TLR-2 and TLR-4 in the area of induced ischemia. The decreased NF-κB phosphorylation by EP treatment upon reperfusion was associated with diminished tumor necrosis factor-α, interleukin (IL)-1β, and IL-6 expression under hyperglycemia. EP treatment upon reperfusion also attenuated I/R-related down-regulation of Bcl-2 and up-regulation of Bax, and decreased I/R-induced cardiomyocytes apoptosis. In conclusion, EP treatment upon reperfusion conveyed significant myocardial protection against the myocardial I/R injury under both normoglycemic and hyperglycemic conditions. Associated mechanisms involved attenuated increase in HMGB1 level and suppression of its down-stream pathways, which were common to both glycemic conditions.
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1. College of Medicine (의과대학) > Dept. of Anesthesiology and Pain Medicine (마취통증의학교실) > 3. Dissertation
Yonsei Authors
Soh, Sa Rah(소사라) ORCID logo https://orcid.org/0000-0001-5022-4617
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