Department of Anesthesiology, Beijing Obstetrics and Gynecology Hospital, Capital Medical University, Beijing, China.
Eur Rev Med Pharmacol Sci. 2019 Jul;23(14):6339-6345. doi: 10.26355/eurrev_201907_18457.
The aim of this study was to investigate the effect of propofol (PPF) on myocardial ischemia-reperfusion injury (MIRI) by inhibiting the Janus kinase/signal transducer and activator of transcription (JAK/STAT) pathway, and to explore the possible underlying mechanism.
A total of 60 Sprague-Dawley (SD) rats were randomly divided into 5 groups, including the Sham group (n=12), the MIRI model group (n=12), the PPF pretreatment group (n=12), the RG81640-CH (RG) pretreatment group (n=12) and the PPF+RG pretreatment group (n=12). The hemodynamic parameters of rats in each group were measured. Serum samples were collected from rats in each group. Meanwhile, the levels of lactate dehydrogenase (LDH), creatine kinase-muscle/brain (CK-MB), nicotinamide adenine dinucleotide+ (NAD+) and inflammatory factors, including tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6) and monocyte chemotactic protein (MCP), were detected by enzyme-linked immunosorbent assay (ELISA). Myocardial infarction area of rats in each group was detected via 2,3,5-triphenyl tetrazolium chloride (TTC) staining. Moreover, the JAK/STAT pathway, as well as apoptosis indexes in myocardial cells of rats, were detected via Western blotting.
Compared with the Sham group, the contents of LDH, CK-MB, NAD+ and inflammatory factors, as well as the area of myocardial infarction were significantly increased in the MIRI group (p<0.05). In terms of hemodynamic parameters, the left ventricular end-diastolic pressure (LVEDP) was significantly increased in the MIRI group. However, heart rate (HR), left ventricular developed pressure (LVDP) and maximal rate of the increase/decrease of left ventricular pressure (±dp/dtmax) were significantly decreased in the MIRI group when compared with those of the Sham group (p<0.05). Compared with the MIRI group, the contents of LDH, CK-MB, NAD+ and inflammatory factors, as well as the area of myocardial infarction and LVEDP were significantly declined in the PPF group. Meanwhile, HR, LVDP and ±dp/dtmax were remarkably increased (p<0.05). No significant differences in each index were found between the PPF + RG group and the MIRI group (p>0.05). Western blotting revealed that the protein level of B-cell lymphoma-2 (Bcl-2) was remarkably increased, while the activity of Caspase-3 was decreased in the PPF group when compared with the MIRI group (p<0.05). In addition, the protein expression levels of JAK1, STAT1 and STAT3 in the PPF group were significantly decreased than those of the MIRI group (p<0.05). However, completely opposite trends were found in the RG group.
PPF reduces the release of inflammatory factors and alleviates tissue damage caused by myocardial apoptosis in MIRI rats by inhibiting the activation of the JAK/STAT pathway. Our findings indicate that PPF has a certain myocardial protective effect on MIRI.
本研究旨在通过抑制 Janus 激酶/信号转导和转录激活因子（JAK/STAT）通路，探讨异丙酚（PPF）对心肌缺血再灌注损伤（MIRI）的影响，并探讨其潜在机制。
共 60 只 Sprague-Dawley（SD）大鼠随机分为 5 组，包括假手术组（n=12）、MIRI 模型组（n=12）、PPF 预处理组（n=12）、RG81640-CH（RG）预处理组（n=12）和 PPF+RG 预处理组（n=12）。测量各组大鼠的血流动力学参数。收集各组大鼠血清样本。同时，采用酶联免疫吸附试验（ELISA）检测乳酸脱氢酶（LDH）、肌酸激酶同工酶-肌肉/脑（CK-MB）、烟酰胺腺嘌呤二核苷酸+（NAD+）和炎症因子，包括肿瘤坏死因子-α（TNF-α）、白细胞介素-6（IL-6）和单核细胞趋化蛋白（MCP）的水平。通过 2,3,5-三苯基氯化四氮唑（TTC）染色检测各组大鼠的心肌梗死面积。此外，通过 Western blot 检测大鼠心肌细胞中 JAK/STAT 通路及细胞凋亡指标。
与假手术组相比，MIRI 组 LDH、CK-MB、NAD+和炎症因子含量以及心肌梗死面积明显增加（p<0.05）。血流动力学参数方面，MIRI 组左心室舒张末期压（LVEDP）明显升高，而心率（HR）、左心室发展压（LVDP）和左心室压力最大上升/下降速率（±dp/dtmax）明显降低（p<0.05）。与 MIRI 组相比，PPF 组 LDH、CK-MB、NAD+和炎症因子含量以及心肌梗死面积和 LVEDP 均显著下降，HR、LVDP 和±dp/dtmax 明显升高（p<0.05）。PPF+RG 组与 MIRI 组各指标比较差异均无统计学意义（p>0.05）。Western blot 显示，与 MIRI 组相比，PPF 组 B 细胞淋巴瘤-2（Bcl-2）蛋白水平显著升高，Caspase-3 活性降低（p<0.05）。此外，PPF 组 JAK1、STAT1 和 STAT3 蛋白表达水平明显低于 MIRI 组（p<0.05）。然而，在 RG 组中发现了完全相反的趋势。
PPF 通过抑制 JAK/STAT 通路的激活，减少 MIRI 大鼠炎症因子的释放，减轻心肌细胞凋亡引起的组织损伤。研究结果表明，PPF 对 MIRI 具有一定的心肌保护作用。
