Department of Anesthesiology and Pain Medicine, Yonsei University College of Medicine, 50 Yonsei-ro, Seodaemun-gu, Seoul, Republic of Korea; Severance Cardiovascular Hospital, 50 Yonsei-ro, Seodaemun-gu, Seoul, Republic of Korea.
Anesthesia and Pain Research Institute, Yonsei University College of Medicine, 50 Yonsei-ro, Seodaemun-gu, Seoul, Republic of Korea.
Int J Cardiol. 2018 Feb 1;252:156-162. doi: 10.1016/j.ijcard.2017.11.038. Epub 2017 Nov 21.
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.
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.
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.
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.
高血糖（HG）通过增强高迁移率族蛋白 B1（HMGB1）的释放加剧心肌缺血/再灌注（I/R）损伤，并使保护策略无效，从而放大炎症反应。本研究在与临床相关的 HG 条件下，研究了乙基丙酮酸（EP）对心肌 I/R 损伤的作用。
将 Sprague-Dawley 大鼠（n=76）随机分为 6 组：正常血糖（NG）-假手术组、NG-I/R-对照组（C，生理盐水）、再灌注时给予 EP 治疗（50mg/kg）、HG-假手术组、HG-I/R-对照组和再灌注时给予 EP 治疗。HG 通过 1.2g/kg 葡萄糖诱导。I/R 通过结扎左前降支 30min 后再灌注 4h 诱导。
与 NG 相比，HG 导致 I/R 后心肌梗死面积增加 19%，HMGB1-受体的晚期糖基化终产物/ Toll 样受体-NF-κB 通路的激活也增加，而 EP 可减弱这种作用。EP 治疗与肿瘤坏死因子-α、白细胞介素-1β 和白细胞介素-6 的表达减少有关。它还可以使促凋亡 Bax 蛋白的增加和抗凋亡 Bcl-2 蛋白的减少正常化。这些作用与心肌凋亡和梗死面积的减少有关（在 NG 和 HG 组分别减少 30%和 36%），而与血糖状况无关。
HG 通过增加 HMGB1 水平放大炎症反应，加重心肌 I/R 损伤。再灌注时给予 EP 治疗，无论血糖状况如何，对 NG 和 HG 条件下的 I/R 损伤均具有显著的心肌保护作用。在这两种血糖条件下，共同的机制包括减轻 HMGB1 水平的增加和抑制其下游途径。
