CRCardiovascular Reviews3083-48802981-8109Bio-Byword Scientific Publishing Pty. Ltd.10.26689/CR.v4i3.15625ArticleMetformin Improves Myocardial Fibrosis in Spontaneously Hypertensive Rats via the TGF-β/Smads Signaling Pathwayhttps://artdesignp.com/journal/CR/4/3/10.26689/CR.v4i3.15625ZhaoHong,ZhaoWenfei,JinQian,WangCong2026432026-09-30Objective: Effects of metformin on myocardial fibrosis in spontaneously hypertensive rats. Method: Twenty spontaneously hypertensive rats (SHR) were randomly divided into a model group and a metformin treatment group, with 10 rats in each group. The control group consisted of 8 Wistar-Kyoto (WKY) rats. In the treatment group, metformin was administered intragastrically for six months at a dose of 100 mg/kg /d, and the rats were fed a high-fat, high-sugar diet. The model group and the control group were administered gastric irrigation with the same amount of physiological saline. During the period, body weight was monitored every week, and blood pressure was recorded every seven weeks. Echocardiography was performed before sampling. The heart tissue of rats was taken, and a part of the heart tissue was fixed in formalin. The paraffin wax embedding method was used. Sirius red staining of pathological sections was performed to observe myocardial cells and calculate myocardial collagen volume fraction (CVF). In the other part of the heart tissue, TGF-β1, Smad2, Smad3, and Smad7 proteins were analyzed by Western blotting. Results: In the statistical comparative analysis of SBP, DBP, MBP, HR, SV, aortic blood flow velocity, pulmonary artery flow velocity, and mitral blood flow velocity in the metformin group, there was no significant difference between the treatment group and the SHR group. However, metformin intervention in SHR significantly improved EF, FS, heart weight, myocardial fibrosis, and myocardial cell hypertrophy. In the comparison map of FS, EF, and heart weight, there were significant differences between the metformin group and the SHR group. EF and FS of hypertensive rats were significantly lower than those of healthy rats, and SHR rats in the metformin treatment group were significantly higher than those in the model group. It can be seen from the comparison results of cardiac weight and pathological sections that metformin inhibits hypertension-induced myocardial hypertrophy, cardiac mass gain, and myocardial fibrosis. Western Blot results show that metformin can inhibit TGF-β / Smads signaling pathway. Conclusion: Metformin ameliorates hypertension-induced myocardial fibrosis in SHR rats by inhibiting TGF-β/Smads signaling pathway.Metformin, SHR, Myocardial fibrosis

[1]   Frangogiannis NG, 2021, Cardiac Fibrosis. Cardiovascular Research, 17(6): 1450–1488. [2]   Huang S, Chen B, Humeres C, Alex L, Hanna A, Frangogiannis NG, 2020, The Role of Smad2 and Smad3 in Regulating Homeostatic Functions of Fibroblasts In Vitro and in Adult Mice. Biochimica et Biophysica Acta - Molecular Cell Research, 1867(7): 118703. [3]   Kononova YA, Likhonosov NP, Babenko AY, 2022, Metformin: Expanding the Scope of Application—Starting Earlier than Yesterday, Canceling Later. International Journal of Molecular Sciences, 23(4): 2363. [4]   Chen R, Feng Y, Wu J, Song Y, Li H, Shen Q, Li D, Zhang J, Lu Z, Xiao H, Zhang Y, 2018, Metformin Attenuates Angiotensin II-Induced TGFβ1 Expression by Targeting Hepatocyte Nuclear Factor-4-α. British Journal of Pharmacology, 175(8): 1217–1229. [5]   Yang X, Xu Z, Zhang C, Cai Z, Zhang J, 2017, Metformin, Beyond an Insulin Sensitizer, Targeting Heart and Pancreatic β Cells. Biochimica et Biophysica Acta - Molecular Basis of Disease, 1863(8): 1984–1990. [6]   Lu J, Zhang J, Lyu Y, Wang B, Jia L, Shi J, 2020, Molecular Signaling Mechanism of Metformin Inhibiting Collagen Production in Rat Biliary Fibroblasts. Journal of Southern Medical University, 40(5): 640–646. [7]   Xiao H, Ma X, Feng W, Fu Y, Lu Z, Xu M, Shen Q, Zhu Y, Zhang Y, 2010, Metformin Attenuates Cardiac Fibrosis by Inhibiting the TGFβ1-Smad3 Signaling Pathway. Cardiovascular Research, 87(3): 504–513. [8]   Liang Y, Zhao Y, Yang L, Zhao M, 2018, Effects of Metformin on Myocardial Fibrosis Model Rats. Herald of Medicine, 37(11): 1321–1326. [9]   Hu C, 2020, ADAMTS16 Regulates Myocardial Fibrosis and Cardiac Dysfunction by Activating TGF-β1, thesis, Huazhong University of Science and Technology.