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

Abstract

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

CLC Number:

R329.28

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.

Figures/Tables 5

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References 24

[1]	SCHAUB M C， HEFTI M A， HARDER B A， et al. Various hypertrophic stimuli induce distinct phenotypes in cardiomyocytes［J］. J Mol Med， 1997， 75（11/12）： 901-920.
[2]	NAKAMURA M， SADOSHIMA J. Mechanisms of physiological and pathological cardiac hypertrophy［J］. Nat Rev Cardiol， 2018， 15（7）： 387-407.
[3]	HAIDER A W， LARSON M G， BENJAMIN E J， et al. Increased left ventricular mass and hypertrophy are associated with increased risk for sudden death［J］. J Am Coll Cardiol， 1998， 32（5）： 1454-1459.
[4]	SHIMIZU I， MINAMINO T. Physiological and pathological cardiac hypertrophy［J］. J Mol Cell Cardiol， 2016， 97： 245-262.
[5]	SALVATORE T， GALIERO R， CATURANO A， et al. Effects of metformin in heart failure： from pathophysiological rationale to clinical evidence［J］. Biomolecules， 2021， 11（12）： 1834.
[6]	SCHEEN A J， PAQUOT N. Metformin revisited： a critical review of the benefit-risk balance in at-risk patients with type 2 diabetes［J］. Diabetes Metab， 2013， 39（3）： 179-190.
[7]	MASOUDI F A， INZUCCHI S E， WANG Y F， et al. Thiazolidinediones， metformin， and outcomes in older patients with diabetes and heart failure： an observational study［J］. Circulation， 2005， 111（5）： 583-590.
[8]	CAMPAGNOLI L I M， VARESI A， FAHMIDEH F， et al. From diabetes to degenerative diseases： the multifaceted action of metformin［J］. Int J Mol Sci， 2025， 26（19）： 9748.
[9]	SALVATORE T， PAFUNDI P C， GALIERO R， et al. Can metformin exert as an active drug on endothelial dysfunction in diabetic subjects？［J］. Biomedicines， 2020， 9（1）： 3.
[10]	YANG X， XU Z P， ZHANG C L， et al. Metformin， beyond an insulin sensitizer， targeting heart and pancreatic β cells［J］. Biochim Biophys Acta Mol Basis Dis， 2017， 1863（8）： 1984-1990.
[11]	BAHARDOUST M， MOUSAVI S， YARIALI M， et al. Effect of metformin （vs. placebo or sulfonylurea） on all-cause and cardiovascular mortality and incident cardiovascular events in patients with diabetes： an umbrella review of systematic reviews with meta-analysis［J］. J Diabetes Metab Disord， 2023， 23（1）： 27-38.
[12]	SCHERNTHANER G， BRAND K， BAILEY C J. Metformin and the heart： Update on mechanisms of cardiovascular protection with special reference to comorbid type 2 diabetes and heart failure［J］. Metabolism， 2022， 130： 155160.
[13]	蔡璟浩，周健. 《2021年美国糖尿病学会糖尿病医学诊疗标准》解读［J/OL］. 中国医学前沿杂志（电子版）， 2021， 13（2）： 13-23.
[14]	GRIFFIN S J， LEAVER J K， IRVING G J. Impact of metformin on cardiovascular disease： a meta-analysis of randomised trials among people with type 2 diabetes［J］. Diabetologia， 2017， 60（9）： 1620-1629.
[15]	INZUCCHI S E， MASOUDI F A， WANG Y F， et al. Insulin-sensitizing antihyperglycemic drugs and mortality after acute myocardial infarction： insights from the National Heart Care Project［J］. Diabetes Care， 2005， 28（7）： 1680-1689.
[16]	RUSKOAHO H. Regression of cardiac hypertrophy with drug treatment in spontaneously hypertensive rats［J］. Med Biol， 1984， 62（5）： 263-276.
[17]	ENGELMANN G L， VITULLO J C， GERRITY R G. Morphometric analysis of cardiac hypertrophy during development， maturation， and senescence in spontaneously hypertensive rats［J］. Circ Res， 1987， 60（4）： 487-494.
[18]	CONRAD C H， BROOKS W W， HAYES J A， et al. Myocardial fibrosis and stiffness with hypertrophy and heart failure in the spontaneously hypertensive rat［J］. Circulation， 1995， 91（1）： 161-170.
[19]	黄德盛，赵亚楠，陈云，等. 二甲双胍对H9C2心肌细胞肥大的改善作用及其机制［J］. 吉林大学学报（医学版）， 2023， 49（3）： 675-681.
[20]	SUN D， YANG F. Metformin improves cardiac function in mice with heart failure after myocardial infarction by regulating mitochondrial energy metabolism［J］. Biochem Biophys Res Commun， 2017， 486（2）： 329-335.
[21]	MOHSIN A A， CHEN Q， QUAN N H， et al. Mitochondrial complex Ⅰ inhibition by metformin limits reperfusion injury［J］. J Pharmacol Exp Ther， 2019， 369（2）： 282-290.
[22]	XU M， LI L P， HE X， et al. Metformin induction of heat shock factor 1 activation and the mitochondrial unfolded protein response alleviate cardiac remodeling in spontaneously hypertensive rats［J］. FASEB J， 2024， 38（9）： e23654.
[23]	MAGHRABY N， EL-BAZ M A H， HASSAN A M A， et al. Metformin alleviates doxorubicin-induced cardiotoxicity via preserving mitochondrial dynamics balance and calcium homeostasis［J］. Appl Biochem Biotechnol， 2025， 197（4）： 2713-2733.
[24]	DI NOTTIA M， VERRIGNI D， TORRACO A， et al. Mitochondrial dynamics： molecular mechanisms， related primary mitochondrial disorders and therapeutic approaches［J］. Genes， 2021， 12（2）： 247.

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^△

Improvement effect of metformin on myocardial hypertrophy in spontaneously hypertensive rats and its mechanism

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