瑞马唑仑调节EPAC1/RAP1信号通路对急性心肌梗死大鼠心肌损伤的影响

doi:10.11958/20230890

天津医药 ›› 2024, Vol. 52 ›› Issue (5): 475-479.doi: 10.11958/20230890

瑞马唑仑调节EPAC1/RAP1信号通路对急性心肌梗死大鼠心肌损伤的影响

肖锦亮(), 汪威廉, 但家朋^△()

荆州市中心医院（长江大学附属荆州医院）麻醉科（邮编434000）

收稿日期:2023-06-12 修回日期:2023-10-19 出版日期:2024-05-15 发布日期:2024-05-09
通讯作者: ^△E-mail：cunganiv51@163.com
作者简介:肖锦亮（1983），男，主治医师，主要从事心脏大血管麻醉方面研究。E-mail：ijpr9v@163.com
基金资助:
荆州市2020年医疗卫生科技计划项目(2020HC05)

Effect of remimazolam on myocardial injury in rats with acute myocardial infarction by regulating the EPAC1/RAP1 signaling pathway

XIAO Jinliang(), WANG Weilian, DAN Jiapeng^△()

Department of Anesthesiology, Jingzhou Central Hospital (Jingzhou Hospital Affiliated to Changjiang University), Jingzhou 434000, China

Received:2023-06-12 Revised:2023-10-19 Published:2024-05-15 Online:2024-05-09
Contact: ^△E-mail：cunganiv51@163.com

肖锦亮, 汪威廉, 但家朋. 瑞马唑仑调节EPAC1/RAP1信号通路对急性心肌梗死大鼠心肌损伤的影响[J]. 天津医药, 2024, 52(5): 475-479.

XIAO Jinliang, WANG Weilian, DAN Jiapeng. Effect of remimazolam on myocardial injury in rats with acute myocardial infarction by regulating the EPAC1/RAP1 signaling pathway[J]. Tianjin Medical Journal, 2024, 52(5): 475-479.

摘要/Abstract

摘要：

目的探讨瑞马唑仑调节环腺苷酸激活的交换蛋白1（EPAC1）/RAS相关蛋白1（RAP1）信号通路对急性心肌梗死（AMI）大鼠心肌损伤的影响。方法将大鼠按照随机数字表法分为假手术组、模型组、瑞马唑仑组、瑞马唑仑+8-CPT（EPAC1的激动剂）组，每组20只。除假手术组外，其余各组大鼠通过左前降支结扎法构建AMI大鼠模型；小动物超声仪检测心功能指标；HE染色检测心肌组织病理情况；化学比色法检测大鼠心肌组织超氧化物歧化酶（SOD）和丙二醛（MDA）水平；JC-1染色法检测大鼠心肌细胞线粒体膜电位；TUNEL染色检测心肌细胞TUNEL阳性率；Western blot检测心肌组织EPAC1、RAP1、胱天蛋白酶3（Caspase-3）蛋白表达水平。结果与假手术组相比，模型组大鼠心肌组织结构被严重破坏且浸润大量炎性细胞；心功能指标左心室舒张末期内径（LVEDD）、左心室收缩末期内径（LVESD），心肌组织MDA水平，心肌细胞TUNEL阳性率，心肌组织EPAC1、RAP1、Caspase-3蛋白表达水平均明显升高；左心室射血分数（LVEF）、左心室短轴缩短率（LVFS），心肌组织SOD水平，心肌细胞线粒体膜电位明显降低（P<0.05）。与模型组相比，瑞马唑仑组大鼠心肌损伤缓解，炎性细胞浸润减轻，心功能指标LVEDD、LVESD，心肌组织MDA水平，心肌细胞TUNEL阳性率，心肌组织EPAC1、RAP1、Caspase-3蛋白表达水平均明显降低；LVEF、LVFS，心肌组织SOD水平，心肌细胞线粒体膜电位明显升高（P<0.05）。EPAC1的激动剂减弱了瑞马唑仑对AMI大鼠心肌损伤的缓解作用。结论瑞马唑仑可能通过抑制EPAC1/RAP1信号通路抑制心肌细胞凋亡，减轻AMI大鼠心肌损伤。

关键词: 心肌梗死, 心肌损伤, 瑞马唑仑, 环腺苷酸激活的交换蛋白1, RAS相关蛋白1

Abstract:

Objective To investigate the effect of remimazolam on myocardial injury in rats with acute myocardial infarction (AMI) by regulating exchange proteins directly activated by cAMP (EPAC1)/RAS-related protein 1 (RAP1) signaling pathway. Methods Rats were divided into the sham operation group, the model group, the remazolam group and the remazolam+8-CPT (EPAC1 agonist) group according to random number table method, with 20 rats in each group. Except for the sham operation group, AMI rat model was constructed by ligation of left anterior descending branch in the other groups. Ultrasonic apparatus for small animals was applied to detect cardiac function indicators. HE staining was applied to detect the pathological condition of myocardial tissue. Chemical colorimetry was applied to detect levels of superoxide dismutase (SOD) and malondialdehyde (MDA) in myocardial tissue of rats. JC-1 staining method was applied to detect the mitochondrial membrane potential of rat cardiomyocytes. TUNEL staining was used to detect the TUNEL positive rate of myocardial cells. Western blot assay was applied to detect expression levels of EPAC1, RAP1 and Caspase-3 proteins in myocardial tissue. Results Compared with the sham operation group, the myocardial tissue structure of rats in the model group was severely damaged and infiltrated with a large number of inflammatory cells. Cardiac function indicators left ventricular end diastolic diameter (LVEDD), left ventricular end systolic diameter (LVESD), myocardial tissue MDA level, myocardial cell TUNEL positive rate, and myocardial tissue EPAC1, RAP1 and Caspase-3 protein expression levels were obviously increased, and the left ventricular ejection fraction (LVEF), left ventricular fraction shortening (LVFS), myocardial tissue SOD level, cardiomyocytes mitochondrial membrane potential were obviously decreased (P<0.05). Compared with the model group, the myocardial tissue structure of rats in the ramazolam group was obviously restored, and inflammatory cell infiltration was reduced. The cardiac function indicators LVEDD, LVESD, myocardial tissue MDA level, myocardial cell TUNEL positive rate, and myocardial tissue EPAC1, RAP1 and Caspase-3 protein expression levels were obviously decreased, and LVEF, LVFS, myocardial tissue SOD level, cardiomyocytes mitochondrial membrane potential were obviously increased (P<0.05). Agonists of EPAC1 attenuated the mitigating effect of remazolam on myocardial injury in AMI rats. Conclusion Remimazolam may inhibit the EPAC1/RAP1 signaling pathway, inhibit myocardial cell apoptosis and alleviate myocardial injury in AMI rats.

Key words: myocardial infarction, myocardial damage, remimazolam, exchange proteins directly activated by cAMP, RAS-related

中图分类号:

R542.22

图/表 8

表1 各组大鼠心功能指标比较（n=20，$\bar{x}±s$）

Tab.1 Comparison of cardiac function indexes of rats between the four groups

组别	LVEDD/mm	LVESD/mm	LVEF	LVFS/%
假手术组	6.74±0.65	4.38±0.41	0.79±0.04	44.51±3.23
模型组	11.08±1.20^a	9.64±1.02^a	0.32±0.02^a	15.52±1.46^a
瑞马唑仑组	7.13±0.74^b	4.79±0.52^b	0.70±0.03^b	40.22±3.06^b
瑞马唑仑+ 8-CPT组	10.45±1.01^c	8.91±0.88^c	0.42±0.03^c	20.53±1.96^c
F	116.171^＊＊	264.461^＊＊	1 050.351^＊＊	635.773^＊＊

图1 各组大鼠心肌组织病理损伤情况（HE染色，×200）

Fig.1 Histopathological damage of myocardium of rats in various groups (HE staining, ×200)

表2 各组大鼠心肌组织SOD和MDA水平比较（n=5，$\bar{x}±s$）

Tab.2 Comparison of SOD and MDA levels in rat myocardial tissue between four groups

组别	SOD/（U/mg）	MDA/（μmol/g）
假手术组	48.12±4.45	0.38±0.04
模型组	22.35±2.33^a	0.71±0.07^a
瑞马唑仑组	40.14±4.01^b	0.43±0.05^b
瑞马唑仑+8-CPT组	25.26±2.24^c	0.67±0.06^c
F	64.636^＊＊	44.061^＊＊

表3 各组大鼠心肌细胞线粒体膜电位及TUNEL阳性率比较（n=5，$\bar{x}±s$）

Tab.3 Comparison of mitochondrial membrane potential and TUNEL positive rate of rat myocardial tissue cells between the four groups

组别	红绿荧光比值	TUNEL阳性率/%
假手术组	9.12±0.10	5.22±0.23
模型组	2.23±0.21^a	32.12±3.11^a
瑞马唑仑组	7.54±0.67^b	12.94±1.20^b
瑞马唑仑+8-CPT组	2.48±0.30^c	27.56±2.81^c
F	415.740^＊＊	164.791^＊＊

图2 各组大鼠心肌细胞线粒体膜电位（JC-1染色，×200）

Fig.2 Mitochondrial membrane potential of rat myocardial tissue cells in each group (JC-1 staining, ×200)

图3 各组大鼠心肌细胞凋亡情况（TUNEL染色，×200）

Fig.3 Apoptosis of rat cardiomyocytes in each group of rats (TUNEL staining, ×200)

表4 各组大鼠心肌组织EPAC1、RAP1、Caspase-3蛋白表达水平比较（n=5，$\bar{x}±s$）

Tab.4 Comparison of EPAC1, RAP1 and Caspase-3 protein expression levels in rat myocardial tissue between the four groups

组别	EPAC1	RAP1	Caspase-3
假手术组	0.24±0.03	0.17±0.02	0.26±0.03
模型组	1.06±0.11^a	0.96±0.10^a	1.13±0.12^a
瑞马唑仑组	0.41±0.04^b	0.25±0.03^b	0.34±0.05^b
瑞马唑仑+8-CPT组	0.84±0.09^c	0.88±0.08^c	1.02±0.12^c
F	126.072^＊＊	192.279^＊＊	126.268^＊＊

图4 Western blot检测各组大鼠心肌组织EPAC1、RAP1、Caspase-3蛋白表达 A：假手术组；B：模型组；C：瑞马唑仑组；D：瑞马唑仑+8-CPT组。

Fig.4 Western blot analysis of EPAC1, RAP1 and Caspase-3 protein expression in rat myocardial tissue in each group

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瑞马唑仑调节EPAC1/RAP1信号通路对急性心肌梗死大鼠心肌损伤的影响

Effect of remimazolam on myocardial injury in rats with acute myocardial infarction by regulating the EPAC1/RAP1 signaling pathway

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