Magnesium isoglycyrrhizinate ameliorates isoproterenol-induced myocardial remodeling in mice by regulating oxidative stress and apoptosis via the PI3K/AKT1 signaling pathway

doi:10.5246/jcps.2025.04.024

Abstract

Abstract:

The aim of this study is to investigate the mechanism of magnesium isoglycyrrhizinate (MgIG) in the treatment of myocardial remodeling induced by isoproterenol (ISO) in mice. We assessed the impact of MgIG on ISO-induced myocardial remodeling by activating the PI3K/AKT1 pathway. The cardiac function of mice was evaluated by echocardiography, revealing that MgIG could improve left ventricular function. Pathological staining analysis showed that MgIG could reduce the degree of myocardial injury caused by ISO. Serum data detected by ELISA demonstrated that MgIG could decrease the levels of CK-MB, MDA, and LDH while increasing the activity of GSH-Px. Western blotting analysis revealed that protein expression levels of Collagen I, BNP, Bax, cleaved caspase-3, p-PI3K, and p-AKT1 were decreased, whereas the protein expressions of Bcl-2, COX2, and SOD1 were increased upon MgIG treatment. However, the activation of the PI3K pathway reversed the cardioprotective effects of MgIG, as evidenced by the addition of PI3K activators. Taken together, our comprehensive results suggested that MgIG could improve ISO-induced myocardial remodeling, potentially through its mechanism of inhibiting the PI3K/AKT1 pathway to regulate apoptosis and oxidative stress.

Key words: Magnesium isoglycyrrhizinate, Isoproterenol, Myocardial remodeling, PI3K/AKT1, Apoptosis, Oxidative stress

Supporting: /attached/file/20250502/20250502173655_429.pdf

Xingyu Zhou, Dan Fu, Saige Sun, Qiuyan Liu, Longxing Liu, Jia Shi, Zijie Ge, Yu Ma, Yilin He, Li Xu, Kai Qian. Magnesium isoglycyrrhizinate ameliorates isoproterenol-induced myocardial remodeling in mice by regulating oxidative stress and apoptosis via the PI3K/AKT1 signaling pathway[J]. Journal of Chinese Pharmaceutical Sciences, 2025, 34(4): 321-333.

Figures/Tables 7

References 34

[1]	Forno, E.; Han, Y.Y.; Mullen, J.; Celedón, J.C. Overweight, obesity, and lung function in children and adults-a meta-analysis. J. Allergy Clin. Immunol. Pract. 2018, 6, 570–581.e10.
[2]	Li, R.; Song, L.; Liu, J.; Bai, Y.; Du, Y.; Lin, C.; Su, X.; Yu, Z. Cardioprotective effect of Linagliptin on diabetic Wistar rats. J. Chin. Pharm. Sci. 2021, 30, 334–346.
[3]	Li, W.W.; Yang, J.C.; Lyu, Q.F.; Wu, G.F.; Lin, S.M.; Yang, Q.H.; Hu, J.M. Taurine attenuates isoproterenol-induced H9c2 cardiomyocytes hypertrophy by improving antioxidative ability and inhibiting calpain-1-mediated apoptosis. Mol. Cell Biochem. 2020, 469, 119–132.
[4]	Zhang, Y.; Chen, W.Z.; Wang, Y. STING is an essential regulator of heart inflammation and fibrosis in mice with pathological cardiac hypertrophy via endoplasmic reticulum (ER) stress. Biomed. Pharmacother. 2020, 125, 110022.
[5]	Vuda, M.; Kamath, A. Drug induced mitochondrial dysfunction: Mechanisms and adverse clinical consequences. Mitochondrion. 2016, 31, 63–74.
[6]	Park, S.; Yoon, J.; Bae, S.; Park, M.; Kang, C.S.; Ke, Q.G.; Lee, D.; Kang, P.M. Therapeutic use of H₂O₂-responsive anti-oxidant polymer nanoparticles for doxorubicin-induced cardiomyopathy. Biomaterials. 2014, 35, 5944–5953.
[7]	Cheng, W.J.; Shi, X.Q.; Zhang, J.C.; Li, L.Y.; Di, F.Q.; Li, M.; Wang, C.T.; An, Q.; Zhao, D. Role of PI3K-AKT pathway in ultraviolet ray and hydrogen peroxide-induced oxidative damage and its repair by grain ferments. Foods. 2023, 12, 806.
[8]	Zheng, W.; Li, H.; Luo, L.; Hu, C.; You, P. PI3K/AKT/mTOR pathway inhibition and miR-210-mediated suppression of Atg7 promote autophagy in TOPC-induced apoptosis of H1975 cells. J. Chin. Pharm. Sci. 2023, 32, 881–892.
[9]	Cantley, L.C. The phosphoinositide 3-kinase pathway. Science. 2002, 296, 1655–1657.
[10]	Lu, D.D.; Yang, Y.T.; Du, Y.H.; Zhang, L.; Yang, Y.; Tibenda, J.J.; Nan, Y.; Yuan, L. The potential of glycyrrhiza from "medicine food homology" in the fight against digestive system tumors. Molecules. 2023, 28, 7719.
[11]	Isbrucker, R.A.; Burdock, G.A. Risk and safety assessment on the consumption of Licorice root (Glycyrrhiza sp.), its extract and powder as a food ingredient, with emphasis on the pharmacology and toxicology of glycyrrhizin. Regul. Toxicol. Pharmacol. 2006, 46, 167–192.
[12]	Wei, Z.H.; Sun, X.Q.; He, Q.Q.; Zhao, Y.; Wu, Y.C.; Han, X.; Wu, Z.L.; Chu, X.; Guan, S.J. Nephroprotective effect of magnesium isoglycyrrhizinate against arsenic trioxide-induced acute kidney damage in mice. Exp. Ther. Med. 2022, 23, 276.
[13]	Liu, M.M.; Zheng, B.; Liu, P.P.; Zhang, J.P.; Chu, X.; Dong, C.H.; Shi, J.; Liang, Y.R.; Chu, L.; Liu, Y.S.; Han, X. Exploration of the hepatoprotective effect and mechanism of magnesium isoglycyrrhizinate in mice with arsenic trioxide-induced acute liver injury. Mol. Med. Rep. 2021, 23, 438.
[14]	Asghari, A.A.; Mahmoudabady, M.; Mousavi Emadi, Z.; Hosseini, S.J.; Salmani, H. Cardiac hypertrophy and fibrosis were attenuated by olive leaf extract treatment in a rat model of diabetes. J. Food Biochem. 2022, 46, e14494.
[15]	Rai, V.; Sharma, P.; Agrawal, S.; Agrawal, D.K. Relevance of mouse models of cardiac fibrosis and hypertrophy in cardiac research. Mol. Cell Biochem. 2017, 424, 123–145.
[16]	Oka, T.; Akazawa, H.; Naito, A.T.; Komuro, I. Angiogenesis and cardiac hypertrophy: maintenance of cardiac function and causative roles in heart failure. Circ. Res. 2014, 114, 565–571.
[17]	Benjamin, I.J.; Jalil, J.E.; Tan, L.B.; Cho, K.; Weber, K.T.; Clark, W.A. Isoproterenol-induced myocardial fibrosis in relation to myocyte necrosis. Circ. Res. 1989, 65, 657–670.
[18]	Yuan, M.; Zhao, B.; Jia, H.; Zhang, C.; Zuo, X. Sinomenine ameliorates cardiac hypertrophy by activating Nrf2/ARE signaling pathway. Bioengineered. 2021, 12, 12778–12788.
[19]	Li, Y.; Zhou, W.W.; Sun, J.H.; Yang, H.X.; Xu, G.R.; Zhang, Y.; Song, Q.H.; Zhang, C.; Liu, W.Z.; Liu, X.C.; Li, A.Y. Modified citrus pectin prevents isoproterenol-induced cardiac hypertrophy associated with p38 signalling and TLR4/JAK/STAT3 pathway. Biomed. Pharmacother. 2021, 143, 112178.
[20]	Zheng, J.; Wu, G.; Hu, G.X.; Peng, Y.Z.; Xiong, X.J. Protective effects against and potential mechanisms underlying the effect of magnesium isoglycyrrhizinate in hypoxia-reoxygenation injury in rat liver cells. Genet. Mol. Res. 2015, 14, 15453–15461.
[21]	Rona, G.; Kahn, D.S.; Chappel, C.I. Studies on infarct-like myocardial necrosis produced by isoproterenol: a review. Rev. Can. Biol. 1963, 22, 241–255.
[22]	Jiang, W.J.; Liu, J.Y.; Li, P.J.; Lu, Q.F.; Pei, X.; Sun, Y.L.; Wang, G.J.; Hao, K. Magnesium isoglycyrrhizinate shows hepatoprotective effects in a cyclophosphamide-induced model of hepatic injury. Oncotarget. 2017, 8, 33252–33264.
[23]	Zhou, Q.L.; Meng, G.W.; Teng, F.; Sun, Q.; Zhang, Y.S. Effects of astragalus polysaccharide on apoptosis of myocardial microvascular endothelial cells in rats undergoing hypoxia/reoxygenation by mediation of the PI3K/Akt/eNOS signaling pathway. J. Cell Biochem. 2018, 119, 806–816.
[24]	Guo, R.; Ren, J. Alcohol dehydrogenase accentuates ethanol-induced myocardial dysfunction and mitochondrial damage in mice: role of mitochondrial death pathway. PLoS One. 2010, 5, e8757.
[25]	Varghese, R.; George Priya Doss, C.; Kumar, R.S.; Almansour, A.I.; Arumugam, N.; Efferth, T.; Ramamoorthy, S. Cardioprotective effects of phytopigments via multiple signaling pathways. Phytomedicine. 2022, 95, 153859.
[26]	Shen, Y.J.; Wang, X.; Yuan, R.S.; Pan, X.; Yang, X.X.; Cai, J.L.; Li, Y.; Yin, A.W.; Xiao, Q.Q.; Ji, Q.Q.; Li, Y.J.; He, B.; Shen, L.H. Prostaglandin E1 attenuates AngII-induced cardiac hypertrophy via EP3 receptor activation and Netrin-1upregulation. J. Mol. Cell Cardiol. 2021, 159, 91–104.
[27]	Cheng, Y.; Shen, A.L.; Wu, X.Y.; Shen, Z.Q.; Chen, X.P.; Li, J.P.; Liu, L.Y.; Lin, X.Y.; Wu, M.Z.; Chen, Y.Q.; Chu, J.F.; Peng, J. Qingda granule attenuates angiotensin II-induced cardiac hypertrophy and apoptosis and modulates the PI3K/AKT pathway. Biomed. Pharmacother. 2021, 133, 111022.
[28]	Ghafouri-Fard, S.; Khanbabapour Sasi, A.; Hussen, B.M.; Shoorei, H.; Siddiq, A.; Taheri, M.; Ayatollahi, S.A. Interplay between PI3K/AKT pathway and heart disorders. Mol. Biol. Rep. 2022, 49, 9767–9781.
[29]	Wang, J.P.; Luo, X.; Lu, J.X.; Wang, X.; Miao, Y.; Li, Q.C.; Wang, L. Rab22a promotes the proliferation, migration, and invasion of lung adenocarcinoma via up-regulating PI3K/Akt/mTOR signaling pathway. Exp. Cell Res. 2022, 416, 113179.
[30]	Liang, C.X.; Jiang, Y.J.; Sun, L.Z. Vitexin suppresses the proliferation, angiogenesis and stemness of endometrial cancer through the PI3K/AKT pathway. Pharm. Biol. 2023, 61, 581–589.
[31]	Jiang, Y.; Zhang, Q.L.; Bao, J.S.; Du, C.H.; Wang, J.; Tong, Q.; Liu, C. Schisandrin B suppresses glioma cell metastasis mediated by inhibition of mTOR/MMP-9 signal pathway. Biomed. Pharmacother. 2015, 74, 77–82.
[32]	Yu, Y.J.; Zhou, S.Z.; Wang, Y.; Di, S.T.; Wang, Y.L.; Huang, X.; Chen, Y. Leonurine alleviates acetaminophen-induced acute liver injury by regulating the PI3K/AKT signaling pathway in mice. Int. Immunopharmacol. 2023, 120, 110375.
[33]	Sun, H.; Zhou, F.; Wang, Y.; Zhang, Y.; Chang, A.M.; Chen, Q. Effects of beta-adrenoceptors overexpression on cell survival are mediated by Bax/Bcl-2 pathway in rat cardiac myocytes. Pharmacology. 2006, 78, 98–104.
[34]	Yin, Y.; Han, W.; Cao, Y. Association between activities of SOD, MDA and Na⁺-K⁺-ATPase in peripheral blood of patients with acute myocardial infarction and the complication of varying degrees of arrhythmia. Hellenic J. Cardiol. 2019, 60, 366–371.