二甲双胍对自发性高血压大鼠心肌肥厚的改善作用及其机制

doi:10.13481/j.1671-587X.20260211

摘要/Abstract

摘要：

目的探讨二甲双胍（Met）对自发性高血压大鼠（SHR）心肌肥厚的改善作用，并阐明其可能的作用机制。方法以SHR建立心肌肥厚模型，并随机分为SHR组和SHR+Met组；另选取同年龄WKY雄性大鼠作为WKY组。SHR+Met组大鼠给予Met悬浊液（300 mg·kg^-1·d^-1）灌胃6周，SHR组和WKY组大鼠予等体积蒸馏水灌胃。干预结束后，称量各组大鼠体质量和左心室质量，计算左心室质量指数（LVMI）。采用Western blotting法检测各组大鼠心肌组织中心房利钠肽（ANP）和B型脑钠肽（BNP）蛋白表达水平，电镜观察各组大鼠心肌细胞线粒体超微结构，Western blotting法和实时荧光定量PCR（RT-qPCR）法检测各组大鼠心肌组织中线粒体融合指标神经萎缩蛋白1（OPA1）及线粒体融合蛋白2（MFN2）蛋白和mRNA表达水平。结果与WKY组比较，SHR组大鼠LVMI明显升高（P<0.05），心肌组织中ANP和BNP蛋白表达水平明显升高（P<0.05）。与SHR组比较，SHR+Met组大鼠LVMI明显降低（P<0.05），心肌组织中ANP和BNP蛋白表达水平明显降低（P<0.05）。电镜观察，SHR组大鼠心肌组织中线粒体排列紊乱，出现线粒体嵴间隙增宽、断裂或消失；SHR+Met组大鼠线粒体形态有所恢复，嵴重构明显。与WKY组比较，SHR组大鼠心肌组织中OPA1和MFN2蛋白与mRNA表达水平明显降低（P<0.05）；与SHR组比较，SHR+Met组大鼠心肌组织中OPA1和MFN2蛋白与mRNA水平明显升高（P<0.05）。结论 Met可减轻SHR大鼠的心肌肥厚，其作用机制可能与改善线粒体形态、上调心肌组织中线粒体融合蛋白OPA1和MFN2表达有关。

关键词: 心肌肥厚, 二甲双胍, 线粒体融合, 神经萎缩蛋白1, 线粒体融合蛋白2

Abstract:

Objective To discuss the ameliorative effect of metformin （Met） on myocardial hypertrophy in the spontaneously hypertensive rats （SHR）， and to clarify its possible mechanism of action. Methods The myocardial hypertrophy models were established with SHR， and the rats were randomly divided into SHR group and SHR+Met group； the age-matched male WKY rats were selected as WKY group. The rats in SHR+Met group were given Met suspension （300 mg·kg^-1·d^-1） by gavage for 6 weeks， and the rats in SHR group and WKY group were given equal volume of distilled water by gavage. After intervention， the body mass and left ventricular mass of the rats in various groups were measured， and the left ventricular mass index （LVMI） was calculated. Western blotting method was used to detect the expression levels of atrial natriuretic peptide （ANP） and brain natriuretic peptide （BNP） proteins in myocardium tissue of the rats in various groups； electron microscope was used to observe the mitochondrial ultrastructure of the cardiomyocytes of the rats in various groups； Western blotting method and real-time fluorescence quantitative PCR （RT-qPCR） method were used to detect the expression levels of mitochondrial fusion indicators optic atrophy 1 （OPA1） and mitofusin 2 （MFN2） proteins and mRNA in myocardium tissue of the rats in various groups. Results Compared with WKY group， the LVMI of the rats in SHR group was significantly increased （P<0.05）， and the expression levels of ANP and BNP proteins in myocardium tissue of the rats were significantly increased （P<0.05）. Compared with SHR group， the LVMI of the rats in SHR+Met group was significantly decreased （P<0.05）， and the expression levels of ANP and BNP proteins in myocardium tissue of the rats were significantly decreased （P<0.05）. The electron microscope results showed that in SHR group， the mitochondria in myocardium tissue of the rats were arranged disorderly， with widened， broken， or disappeared mitochondrial cristae spaces； in SHR+Met group， the mitochondrial morphology of the rats was partially restored， and the cristae remodeling was obvious. Compared with WKY group， the expression levels of OPA1 and MFN2 proteins and mRNA in myocardium tissue of the rats in SHR group were significantly decreased （P<0.05）； compared with SHR group， the levels of OPA1 and MFN2 proteins and mRNA in myocardium tissue of the rats in SHR+Met group were significantly increased （P<0.05）. Conclusion Met can alleviate myocardial hypertrophy in the SHR rats， and its mechanism may be related to improving mitochondrial morphology and up-regulating the expression of mitochondrial fusion proteins OPA1 and MFN2 in the myocardium tissue.

Key words: Myocardial hypertrophy, Metformin, Mitochondrial fusion, Optic atrophy 1, Mitofusin 2

中图分类号:

R329.28

刘谋杰,张静,武慧慧,谢菊华. 二甲双胍对自发性高血压大鼠心肌肥厚的改善作用及其机制[J]. 吉林大学学报(医学版), 2026, 52(2): 391-397.

Moujie LIU,Jing ZHANG,Huihui WU,Juhua XIE. Improvement effect of metformin on myocardial hypertrophy in spontaneously hypertensive rats and its mechanism[J]. Journal of Jilin University(Medicine Edition), 2026, 52(2): 391-397.

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Gene	Forward	Reverse
OPA1	5'-GTAGTGGTTGGGGTCCTTCC-3'	5'-AAGCTCTGTGTATTGAGTGCAGC-3'
MFN2	5'-ATGCCACCCTTGCCACAG-3'	5'-TCCTCCGACCACGAGAAT-3'
GAPDH	5'-ACAGCAACAGGGTGGTGGAC-3'	5'-TTTGAGGGTGCAGCGAACTT-3'

Group	Body weight（m/g）	LVM（m/g）	LVMI（η/%）
WKY	293.70±20.64	0.67±0.08	0.23±0.01
SHR	283.20±18.80	0.79±0.05	0.28±0.01^*
SHR+Met	272.00±18.54	0.66±0.11	0.24±0.03^△