Department of Surgery, University of Virginia Health System, Charlottesville, Virginia.
Department of Radiology, University of Virginia Health System, Charlottesville, Virginia.
J Surg Res. 2024 Sep;301:554-562. doi: 10.1016/j.jss.2024.06.023. Epub 2024 Jul 24.
Acute hyperglycemia (HG) enhances inflammatory and oxidative stress and exacerbates myocardial infarct size during ischemia-reperfusion injury by activating splenic leukocytes. Formyl peptide receptor 1 (FPR1) on leukocytes is activated by and mediates myocardial ischemia-reperfusion injury. We hypothesize that selective FPR1 antagonist cinnamoyl-F-(D)L-F-(D)L-F (CF) or potent reducing agent tris (2-carboxyethyl) phosphine hydrochloride (TCEP) could abrogate hyperglycemic infarct exacerbation, both alone and synergistically via a novel CF-TCEP compound that would target leukocytes for antioxidative effect.
Acute HG was induced in wild type mice with an intraperitoneal dextrose injection followed by left coronary artery occlusion (30 min) and reperfusion (60 min). In treatment groups, CF (0.1 mg/kg or 1 mg/kg), TCEP (1 mg/kg or 20 mg/kg), or the CF-TCEP conjugate (0.1 mg/kg) was administered intravenously before reperfusion. The hearts were harvested to measure infarct size (IF).
HG resulted in >50% increase in IF compared to euglycemic mice (52.1 ± 3.0 versus 34.0 ± 3.2%, P < 0.05). Neither CF nor TCEP independently exerted an infarct-sparing effect at lower doses (46.2 ± 2.1% or 50.9 ± 4.1%, P > 0.05 versus HG control) but at high doses, significantly attenuated IF exacerbation (23.2 ± 5.2% or 33.9 ± 3.6%, P < 0.05 versus HG control). However, the low-dose CF-TCEP conjugate significantly reduced IF (39.1 ± 1.7%, P < 0.05 versus HG control). IF was decreased to near euglycemic control levels (P > 0.05).
The CF-TECP conjugate synergistically attenuated HG infarct exacerbation at significantly lower respective doses of CF and TCEP. In addition to the intrinsic anti-inflammatory effect of blocking FPR1, CF is also a feasible tool for leukocyte-targeted therapy to treat IRI.
急性高血糖（HG）通过激活脾白细胞，增强炎症和氧化应激，并在缺血再灌注损伤期间加剧心肌梗死面积。白细胞上的甲酰肽受体 1（FPR1）被激活并介导心肌缺血再灌注损伤。我们假设选择性 FPR1 拮抗剂肉桂酰-F-（D）L-F-（D）L-F（CF）或强效还原剂三（2-羧乙基）膦盐酸盐（TCEP）可以单独或通过一种新型 CF-TCEP 化合物协同拮抗高血糖性梗死加重，该化合物将针对白细胞发挥抗氧化作用。
通过腹腔注射葡萄糖诱导野生型小鼠急性 HG，随后进行左冠状动脉闭塞（30 分钟）和再灌注（60 分钟）。在治疗组中，在再灌注前静脉内给予 CF（0.1mg/kg 或 1mg/kg）、TCEP（1mg/kg 或 20mg/kg）或 CF-TCEP 缀合物（0.1mg/kg）。收获心脏以测量梗死面积（IF）。
与正常血糖小鼠相比，HG 导致 IF 增加超过 50%（52.1±3.0%与 34.0±3.2%，P<0.05）。CF 或 TCEP 单独在低剂量时均未发挥梗死保护作用（46.2±2.1%或 50.9±4.1%，P>0.05 与 HG 对照），但在高剂量时，可显著减轻 IF 加重（23.2±5.2%或 33.9±3.6%，P<0.05 与 HG 对照）。然而，低剂量 CF-TCEP 缀合物可显著降低 IF（39.1±1.7%，P<0.05 与 HG 对照），使 IF 降低至接近正常血糖控制水平（P>0.05）。
CF-TCEP 缀合物以明显较低的 CF 和 TCEP 各自剂量协同减轻 HG 梗死加重。除了阻断 FPR1 的固有抗炎作用外，CF 也是一种针对白细胞的靶向治疗工具，可用于治疗 IRI。
