Cardioprotective action of metformin in experimental isoproterenol-induced myocardial infarction
DOI:
https://doi.org/10.11603/bmbr.2706-6290.2022.2.12890Keywords:
metformin, myocardial infarction, hypertrophy, fibrosisAbstract
Summary. Myocardial infarction (MI) occurs more frequently in patients with diabetes mellitus (DM) than in the general population and is characterized by a less favorable prognosis. Metformin is a first-line drug for the treatment of type 2 diabetes, which is known for its pronounced cardioprotective effect.
The aim of the study – to investigate the antihypertrophic and antiapoptotic effects of metformin and its effect on the expression of brain natriuretic peptide (BNP) in isoproterenol (Iso) induced MI.
Materials and Methods. The study was performed on 50 white adult male rats. MI was induced by 2 injections of Iso (100 mg/kg) with 24 hours interval. Treatment with metformin (200 mg/kg) was performed for 7 days from the first day of the experiment. Histological sections of the myocardium were stained with hematoxylin and eosin. BNP expression was examined using the Rat BNP ELISA Kit (Elabscience). Statistical comparison of multiple groups was performed by one-way ANOVA followed by a Bonferroni post hoc test.
Results. Rats receiving Iso injections had a twofold increase in cardiomyocyte areas from (230.30±3.64) μm2 in (C) group to (490.6±8.93) μm2 in (Iso) group. Metformin treatment prevented hypertrophic changes in cardiomyocytes in MI, as their area remained 58 % smaller. In rats with MI, serum BNP concentrations increased by 77 %: (191.90±8.20) pg/ml in group (Iso) vs (108.0±8.36) pg/ml in control group (C). Metformin treatment reduced BNP concentrations by 29 % to (136.10±2.76) pg/ml in rats with MI. Iso administration resulted in massive accumulation of fibrotic tissue from (0.19±0.01) % in (C) group to (32.08±2.46) % in (Iso) group. Metformin inhibited fibrotic changes in rats with MI by almost 10-fold.
Conclusions. In isoproterenol-induced MI in rats, metformin prevents cardiac hypertrophy, inhibits the expression of the prohypertrophic marker BNP and suppresses fibrotic remodeling.
References
Frey N, Katus HA, Olson EN, Hill JA. Hypertrophy of the Heart: A New Therapeutic Target? Circulation. 2004;109(13): 1580–9. DOI: 10.1161/01.CIR.0000120390.68287.BB.
Dorn GW, Robbins J, Sugden PH. Phenotyping hypertrophy: Eschew obfuscation. Circ Res. 2003;92(11): 1171-5. DOI:10.1161/01.RES.0000077012.11088.BC.
Inthachai T, Lekawanvijit S, Kumfu S, Apaijai N, Pongkan W, Chattipakorn SC, et al. Dipeptidyl peptidase-4 inhibitor improves cardiac function by attenuating adverse cardiac remodelling in rats with chronic myocardial infarction. Exp Physiol. 2015;100(6): 667-79.
DOI: 10.1113/EP085108.
Foretz M, Guigas B, Bertrand L, Pollak M, Viollet B. Metformin: From mechanisms of action to therapies. Cell Metab. 2014;20(6): 953-66.
DOI: 10.1016/j.cmet.2014.09.018.
Eurich DT, Weir DL, Majumdar SR, Tsuyuki RT, Johnson JA, Tjosvold L, et al. Comparative safety and effectiveness of metformin in patients with diabetes mellitus and heart failure systematic review of observational studies involving 34 000 patients. Circ Hear Fail. 2013;6(3): 395-402. DOI: 10.1161/CIRCHEARTFAILURE.112.000162.
Balcıoğlu AS, Müderrisoğlu H. Diabetes and cardiac autonomic neuropathy: Clinical manifestations, cardiovascular consequences, diagnosis and treatment. World J Diabetes. 2015;6(1): 80-91.
DOI: 10.4239/wjd.v6.i1.80.
Ahmed AA, Ahmed AAE, El Morsy EM, Nofal S. Dimethyl fumarate interferes with MyD88-dependent toll-like receptor signalling pathway in isoproterenol-induced cardiac hypertrophy model. J Pharm Pharmacol. 2018;70(11): 1521-30. DOI: 10.1111/jphp.13000.
Ocaranza MP, Díaz-Araya G, Chiong M, Muñoz D, Riveros JP, Ebensperger R, et al. Isoproterenol and angiotensin I-converting enzyme in lung, left ventricle, and plasma during myocardial hypertrophy and fibrosis. J Cardiovasc Pharmacol. 2002;40(2): 246-54. DOI: 10.1097/01.FJC.0000018355.73761.65
Siddiqui MA, Ahmad U, Khan AA, Ahmad M, Badruddeen, Khalid M, et al. Isoprenaline: a Tool for Inducing Myocardial Infarction in Experimental Animals. Int J Pharm. 2016;6(1): 1318-26.
Jensen LO, Maeng M, Thayssen P, Tilsted HH, Terkelsen CJ, Kaltoft A, et al. Influence of diabetes mellitus on clinical outcomes following primary percutaneous coronary intervention in patients with ST-segment elevation myocardial infarction. Am J Cardiol [Internet]. 2012;109(5): 629-35. DOI: 10.1016/j.amjcard.2011.10.018.
Quan He, Guiyun Wu, LaPointe MC. Isoproterenol and cAMP regulation of the human brain natriuretic peptide gene involves Src and Rac. Am J Physiol - Endocrinol Metab. 2000;278: 1115-23.
DOI:10.1152/ajpendo.2000.278.6.E1115.
Nunes S, Soares E, Fernandes J, Viana S, Carvalho E, Pereira FC, et al. Early cardiac changes in a rat model of prediabetes: Brain natriuretic peptide overexpression seems to be the best marker. Cardiovasc Diabetol. 2013;12(1): 1-11. http://www.cardiab.com/content/12/1/44.
Loi H. Ya., Pavliuk B.V., Kramar S.B., Korda M.M. OOM. Metformin exerts cardioprotection in isoproterenol-induced cardiomyopathy in rats. Med Clin Chem. 2019;4: 69-77. DOI: 10.11603/mcch.2410-681X.2019.v.i4.10855.
Van Den Borne SWM, Diez J, Blankesteijn WM, Verjans J, Hofstra L, Narula J. Myocardial remodeling after infarction: The role of myofibroblasts. Nat Rev Cardiol [Internet]. 2010;7(1): 30-7. DOI: 10.1038/nrcardio.2009.199.
Loi H, Kramar S, Laborde C, Marsal D, Pizzinat N, Cussac D, et al. Metformin attenuates postinfarction myocardial fibrosis and inflammation in mice. Int J Mol Sci. 2021;22(17): 9393. DOI: 10.3390/ijms22179393.
Downloads
Published
How to Cite
Issue
Section
License
Copyright (c) 2022 Bulletin of Medical and Biological Research
This work is licensed under a Creative Commons Attribution 4.0 International License.
