异甘草酸镁通过PI3K/AKT1通路调控氧化应激和细胞凋亡改善ISO诱导的小鼠心肌重构

doi:10.5246/jcps.2025.04.024

中国药学(英文版) ›› 2025, Vol. 34 ›› Issue (4): 321-333.DOI: 10.5246/jcps.2025.04.024

异甘草酸镁通过PI3K/AKT1通路调控氧化应激和细胞凋亡改善ISO诱导的小鼠心肌重构

周星宇¹^,², 付丹¹, 孙赛格¹, 刘秋嫣¹, 刘龙兴¹, 石佳¹, 葛子杰¹, 马毓¹, 何艺林³, 徐力³, 钱凯¹^,^*()

^1. 宜春学院, 江西宜春 336000
^2. 泸州市妇幼保健院, 四川泸州 646000
^3. 江西承葛生物科技有限公司, 江西宜春 336000

收稿日期:2024-11-09 修回日期:2025-01-20 接受日期:2025-02-16 出版日期:2025-05-02 发布日期:2025-05-02
通讯作者: 钱凯

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

Xingyu Zhou¹^,², Dan Fu¹, Saige Sun¹, Qiuyan Liu¹, Longxing Liu¹, Jia Shi¹, Zijie Ge¹, Yu Ma¹, Yilin He³, Li Xu³, Kai Qian¹^,^*()

¹ Yichun University, Yichun 336000, Jiangxi, China
² Luzhou Maternal and Child Health Hospital, Luzhou 646000, Sichuan, China
³ Jiangxi Chengge Biotechnology Co., Ltd. Yichun 336000, Jiangxi, China

Received:2024-11-09 Revised:2025-01-20 Accepted:2025-02-16 Online:2025-05-02 Published:2025-05-02
Contact: Kai Qian
Supported by:
Jiangxi Provincial Department of Education Science and Technology Project (Grant No. GJJ2401615); Jiangxi Provincial Department of Education Teaching Reform Project (Grant No. JXJG-24-15-15).

摘要/Abstract

摘要：

本研究旨在异甘草酸镁(MgIG)治疗异丙肾上腺素(ISO)诱导的小鼠心肌重构的作用机制。通过激活PI3K/AKT1通路来评估MgIG对ISO诱导的小鼠心肌重构的结果。通过超声心动图检测小鼠的心脏功能, 发现MgIG可改善左心室功能。病理染色分析显示, MgIG可降低ISO引起的心肌损伤程度。ELISA检测的血清数据显示, MgIG可降低CK-MB、MDA和LDH的含量, 提高GSH-Px的活性。Western blot显示, Collagen I、BNP、Bax、cleaved caspase-3、p-PI3K和p-AKT1蛋白表达降低, 而Bcl-2、COX2和SOD1蛋白表达增加。然而, 当加入PI3K激活剂后, 发现PI3K通路的激活能够逆转MgIG的心脏保护效果。综合结果显示, MgIG可改善ISO诱导的心肌重构, 其机制可能与抑制PI3K/AKT1通路调节细胞凋亡和氧化应激有关。

关键词: 异甘草酸镁, 异丙肾上腺素, 心肌重构, PI3K/AKT1, 细胞凋亡, 氧化应激

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

周星宇, 付丹, 孙赛格, 刘秋嫣, 刘龙兴, 石佳, 葛子杰, 马毓, 何艺林, 徐力, 钱凯. 异甘草酸镁通过PI3K/AKT1通路调控氧化应激和细胞凋亡改善ISO诱导的小鼠心肌重构[J]. 中国药学(英文版), 2025, 34(4): 321-333.

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.

图/表 7

Figure 1. MgIG treatment alleviates ISO-induced cardiac injury and dysfunction in mice. (A) The gross morphological changes of rat heart in each group. (B) Heart weight/body weight (HW/BW) and lung weight/body weight (LW/BW) ratios of rats in each group. (C) The echocardiographic parameters of left ventricular function were displayed by the changes in LVEF and LVFS. (D) H&E staining of mouse hearts at a magnification of 400 (scale =100 μm) in different groups. (E) Masson staining of mouse hearts at a magnification of ×100 in different groups. *Significant difference compared with the Con group, P < 0.05; #significant difference compared with the ISO group, P < 0.05. n = 6 per group.

Figure 2. Effects of MgIG on cardiac phenotype protein. (A) Western blot analysis was used to determine the expression levels of BNP, ANP, β-MHC, Collagen I, and TGF-β. (B–F) Quantitative analysis of BNP, ANP, β-MHC, Collagen I, and TGF-β protein expression. *Significant difference compared with the Con group, P < 0.05; #significant difference compared with the ISO group, P < 0.05. n = 3 per group.

Figure 3. MgIG improves myocardial remodeling by establishing an oxidative defense. (A) The levels of CK-MB, GSH-Px, LDH, and MDA in the serum were evaluated. (B) Western blot analysis was used to determine the expression levels of COX2, CAT, and SOD1. (C–E) Quantitative analysis of COX2, CAT, and SOD1 protein expression. *Significant difference compared with the Con group, P < 0.05; #significant difference compared with the ISO group, P < 0.05. n = 3 per group.

Figure 4. Effects of MgIG on anti-apoptosis and PI3K/AKT1 pathway in cardiac remodeling. (A) Western blot analysis was used to determine the expression levels of Bax, Bcl-2, and cleaved caspase-3. (B–D) Quantitative analysis of Bax, Bcl-2, and cleaved caspase-3 protein expression. (E) Western blot analysis was used to determine the expression levels of p-PI3K and p-AKT1. (F, G) Quantitative analysis of p-PI3K and p-AKT1 protein expression. *Significant difference compared with the Con group, P < 0.05; #significant difference compared with the ISO group, P < 0.05. n = 3 per group.

Figure 5. Activation of PI3K/AKT1 pathway reverses the protective effect of MgIG on cardiac function. (A) The gross morphological changes of rat heart in each group. (B) HW/BW and LW/BW ratios of rats in each group. (C) The echocardiographic parameters of left ventricular function were displayed by the changes in LVEF and LVFS. (D) H&E staining of mouse hearts at a magnification of 400 (scale = 100 μm) in different groups. (E) Masson staining of mouse hearts at a magnification of × 100 in different groups. *Significant difference compared with the Con group, P < 0.05; #significant difference compared with the ISO group, P < 0.05; ^significant difference compared with the ISO + MgIG group, P < 0.05. n = 6 per group.

Figure 6. Activation of the PI3K/AKT1 pathway changed defensive mechanisms and related phenotype proteins in vivo. (A) The levels of CK-MB, GSH-Px LDH, and MDA in the serum were evaluated. (B) Western blot analysis was used to determine the expression levels of BNP, ANP, β-MHC, Collagen I, and TGF-β. (C–G) Quantitative analysis of BNP, ANP, β-MHC, Collagen I, and TGF-β protein expression. *Significant difference compared with the Con group, P < 0.05; #significant difference compared with the ISO group, P < 0.05; ^significant difference compared with the ISO + MgIG group, P < 0.05. n = 3 per group.

Figure 7. The cardioprotective effects of MgIG relies on its antioxidant and anti-apoptosis properties mediated by the PI3K/AKT1 pathway. (A) Western blot analysis was used to determine the expression levels of p-PI3K, p-AKT1, Bax, Bcl-2, CAT, and SOD1. (B–G) Quantitative analysis of p-PI3K, p-AKT1, Bax, Bcl-2, CAT, and SOD1 protein expression. *Significant difference compared with the Con group, P < 0.05; #significant difference compared with the ISO group, P < 0.05; ^significant difference compared with the ISO + MgIG group, P < 0.05. n = 3 per group.

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异甘草酸镁通过PI3K/AKT1通路调控氧化应激和细胞凋亡改善ISO诱导的小鼠心肌重构

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

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