Ginsenoside Rb1 alleviates chronic intermittent hypoxia-induced diabetic cardiomyopathy in db/db mice by regulating the adenosine monophosphate-activated protein kinase/Nrf2/heme oxygenase-1 signaling pathway

  • Bingbing LIU ,
  • Jieru LI ,
  • Jianchao SI ,
  • Qi CHEN ,
  • Shengchang YANG ,
  • Ensheng JI
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  • 1 Department of Physiology, Hebei University of Chinese Medicine, Shijiazhuang 050200, China
    2 Hebei Technology Innovation Center of TCM Combined Hydrogen Medicine, Shijiazhuang 050200, China

Received date: 2022-04-07

  Accepted date: 2022-08-08

  Online published: 2022-12-06

Supported by

Natural Science Foundation of Hebei Province: the Central Regulatory Mechanism of Tanshinone IIA on Angiotensin Ⅱ Induced Sympathetic Excitation in Intermittent Hypoxia(H2019423136);Fundamental Research Funds for the Provisional Universities of Hebei University of Chinese Medicine: a Study on the Protective Mechanism of Hydrogen on Chronic Intermittent Hypoxia-induced Microglia Inflammatory Response(YTZ2019001);a Study on the Molecular Mechanism of Improving Effect Danggui Buxue Decoction on Vascular Endothelial Cell Senescence in Chronic Intermittent Hypoxia through Nrf2/HO-1 Signaling Pathway(YXTD2021005);Graduate Innovation Fund of Hebei University of Chinese Medicine: the Effect of Jinlida Granules on the Myocardial Improvement of Chronic Intermittent Hypoxia Aggravated Diabetic Cardiomyopathy in db/db Mice(XCXZZBS2022013)

Abstract

OBJECTIVE: To examine the protective effect of ginsenoside Rb1 (Rb1), the main component of Renshen (Radix Ginseng), on cardiomyopathy in db/db mice exposed to chronic intermittent hypoxia (CIH) and explore the potential underlying mechanism of Rb1 in treating diabetic cardiomyopathy (DCM).
METHODS: The db/db mice were randomly separated into five groups: normal control group, model group, Rb1 20 mg/kg group, Rb1 40 mg/kg group, and glucagon-like peptide-1 (GLP-1) group. Mice were exposed to air-condition or CIH for 8 weeks, and Rb1 and GLP-1 were administrated before CIH exposure every day. Oral glucose tolerance test (OGTT), intraperitoneal insulin tolerance test (IPITT), total cholesterol (TC), triglyceride (TG), and high-density lipoprotein cholesterol (HDL-C) were detected to evaluate glycolipid metabolism. The level of insulin was detected by a mouse enzyme-linked immunosorbent assay (ELISA). Cardiac function was detected by echocardiography, and myocardial pathology was observed by hematoxylin-eosin and Masson staining. The expression of collagen Ⅰ and collagen Ⅲ was detected by immunohistochemistry. Adenosine monophosphate-activated protein kinase (AMPK)/Nrf2/heme oxygenase-1 (HO-1) signaling pathway was detected by Western blot and immunofluorescence.
RESULTS: Rb1 treatment could improve glucose tolerance and the level of cardiac function indexes, and inhibit the level of oxidative stress indexes and the expression of collagen Ⅰ and collagen Ⅲ. Moreover, Rb1 treatment enhanced AMPK phosphorylation and increased Nrf2 and HO-1 expression.
CONCLUSION: Rb1 treatment alleviated CIH-induced diabetic cardiomyopathy and glycolipid metabolism disorders in db/db mice by inhibiting oxidative stress and regulating the AMPK/Nrf2/HO-1 signaling pathway.

Cite this article

Bingbing LIU , Jieru LI , Jianchao SI , Qi CHEN , Shengchang YANG , Ensheng JI . Ginsenoside Rb1 alleviates chronic intermittent hypoxia-induced diabetic cardiomyopathy in db/db mice by regulating the adenosine monophosphate-activated protein kinase/Nrf2/heme oxygenase-1 signaling pathway[J]. Journal of Traditional Chinese Medicine, 2023 , 43(5) : 906 -914 . DOI: 10.19852/j.cnki.jtcm.20221206.004

References

1. Stanton AM, Vaduganathan M. Asymptomatic diabetic cardiomyopathy: an underrecognized entity in type 2 diabetes. Curr Diab Rep 2021; 21: 41.
2. Uryash A, Mijares A, Flores V, Adams JA, Lopez JR. Effects of naringin on cardiomyocytes from a rodent model of type 2 diabetes. Front Pharmacol 2021; 12: 719268.
3. Xu Q, Tan X, Xian W, et al. Changes of necroptosis in irbesartan medicated cardioprotection in diabetic rats. Diabetes Metab Syndr Obes 2021; 14: 3851-63.
4. Baguet JP, Barone-Rochette G, Tamisier R, Levy P, Pépin JL. Mechanisms of cardiac dysfunction in obstructive sleep apnea. Nat Rev Cardiol 2012; 9: 679-88.
5. Ye L, Chen X, Wang M, et al. Curcumin analogue C 66 attenuates obesity-induced myocardial injury by inhibiting JNK-mediated inflammation. Biomed Pharmacother 2021; 143: 112121.
6. Ciftci TU, Kokturk O, Bukan N, Bilgihan A. The relationship between serum cytokine levels with obesity and obstructive sleep apnea syndrome. Cytokine 2004; 28: 87-91.
7. Mehra R, Benjamin EJ, Shahar E, et al. Association of nocturnal arrhythmias with sleep-disordered breathing: the sleep heart health study. Am J Respir Crit Care Med 2006; 173: 910-6.
8. Wang ZH, Zhu D, Xie S, et al. Inhibition of rho-kinase attenuates left ventricular remodeling caused by chronic intermittent hypoxia in rats via suppressing myocardial inflammation and apoptosis. J Cardiovasc Pharmacol 2017; 70: 102-9.
9. Badran M, Abuyassin B. Uncoupling of vascular nitric oxide synthase caused by intermittent hypoxia. Oxid Med Cell Longev 2016; 2016: 2354870.
10. Takahashi N, Yoshida H, Kimura H, et al. Chronic hypoxia exacerbates diabetic glomerulosclerosis through mesangiolysis and podocyte injury in db/db mice. Nephrol Dial Transplant 2020; 35: 1678-88.
11. Zhang JH, Yang HZ, Su H, et al. Berberine and Ginsenoside Rb1 ameliorate depression-like behavior in diabetic rats. Am J Chin Med 2021; 49: 1195-213.
12. Wang M, Zhang Z. Interventional clinical trials on diabetic peripheral neuropathy: aretrospective analysis. J Pain Res 2021; 14: 2651-64.
13. Luong Huynh D, Nguyen NH, Nguyen CT. Pharmacological properties of ginsenosides in inflammation-derived cancers. Mol Cell Biochem 2021; 476: 3329-40.
14. Hashimoto R, Yu J, Koizumi H, Ouchi Y, Okabe T. Ginsenoside Rb1 prevents MPP(+)-induced apoptosis in PC12 cells by stimulating estrogen receptors with consequent activation of ERK1/2, Akt and inhibition of SAPK/JNK, p38 MAPK. Evid Based Complement Alternat Med 2012; 2012: 693717.
15. Wang J, Qiao L, Li S, Yang G. Protective effect of ginsenoside Rb1 against lung injury induced by intestinal ischemia-reperfusion in rats. Molecules 2013; 18: 1214-26.
16. Huang XP, Qiu YY, Wang B, et al. Effects of Astragaloside Ⅳ combined with the active components of Panax notoginseng on oxidative stress injury and nuclear factor-erythroid 2-related factor 2/heme oxygenase-1 signaling pathway after cerebral ischemia-reperfusion in mice. Pharmacogn Mag 2014; 10: 402-9.
17. Cheng Y, Shen LH, Zhang JT. Anti-amnestic and anti-aging effects of ginsenoside Rg1 and Rb1 and its mechanism of action. Acta Pharmacol Sin 2005; 26: 143-9.
18. Mo C, Wang L, Zhang J, et al. The crosstalk between Nrf2 and AMPK signal pathways is important for the anti-inflammatory effect of berberine in LPS-stimulated macrophages and endotoxin-shocked mice. Antioxid Redox Signal 2014; 20: 574-88.
19. Liu XM, Peyton KJ, Shebib AR, Wang H, Korthuis RJ, Durante W. Activation of AMPK stimulates heme oxygenase-1 gene expression and human endothelial cell survival. Am J Physiol Heart Circ Physiol 2011; 300: H84-93.
20. Kong HL, Wang JP, Li ZQ, Zhao SM, Dong J, Zhang WW. Anti-hypoxic effect of ginsenoside Rbl on neonatal rat cardiomyocytes is mediated through the specific activation of glucose transporter-4 ex vivo. Acta Pharmacol Sin 2009; 30: 396-403.
21. Zhao Y, Yang S, Guo Q, Guo Y, Zheng Y, Ji E. Shashen-Maidong decoction improved chronic intermittent hypoxia-induced cognitive impairment through regulating glutamatergic signaling pathway. J Ethnopharmacol 2021; 274: 114040.
22. Sun ZM, Guan P, Luo LF, et al. Resveratrol protects against CIH-induced myocardial injury by targeting Nrf2 and blocking NLRP 3 inflammasome activation. Life Sci 2020; 245: 117362.
23. Xie Z, Loi Truong T, Zhang P, Xu F, Xu X, Li P. Danqi prescription ameliorates insulin resistance through overall corrective regulation of glucose and fat metabolism. J Ethnopharmacol 2015; 172: 70-9.
24. Yang R, Jiang X, He X, Liang D, Sun S, Zhou G. Ginsenoside Rb1 improves cognitive impairment induced by insulin resistance through Cdk5/p35-NMDAR-IDE pathway. Biomed Res Int 2020; 3905719.
25. Burke SJ, Batdorf HM, Burk DH, et al. db/db Mice exhibit features of human type 2 diabetes that are not present in weight-matched C57BL/6J mice fed a western diet. J Diabetes Res 2017; 2017: 8503754.
26. Chen C, You LJ, Huang Q, et al. Modulation of gut microbiota by mulberry fruit polysaccharide treatment of obese diabetic db/db mice. Food Funct 2018; 9: 3732-42.
27. Zhou S, Yin X, Jin J, et al. Intermittent hypoxia-induced cardiomyopathy and its prevention by Nrf2 and metallothionein. Free Radic Biol Med 2017; 112: 224-39.
28. Fang ZY, Prins JB, Marwick TH. Diabetic cardiomyopathy: evidence, mechanisms, and therapeutic implications. Endocr Rev 2004; 25: 543-67.
29. Bugger H, Abel ED. Molecular mechanisms of diabetic cardiomyopathy. Diabetologia 2014; 57: 660-71.
30. Jia G, DeMarco VG, Sowers JR. Insulin resistance and hyperinsulinaemia in diabetic cardiomyopathy. Nat Rev Endocrinol 2016; 12: 144-53.
31. Guan P, Sun ZM, Wang N, et al. Resveratrol prevents chronic intermittent hypoxia-induced cardiac hypertrophy by targeting the PI3K/AKT/mTOR pathway. Life Sci 2019; 233: 116748.
32. Jia G, Whaley-Connell A, Sowers JR. Diabetic cardiomyopathy: a hyperglycaemia- and insulin-resistance-induced heart disease. Diabetologia 2018; 61: 21-8.
33. Wu P, Chen J, Chen J, et al. Trimethylamine N-oxide promotes apoE(-/-) mice atherosclerosis by inducing vascular endothelial cell pyroptosis via the SDHB/ROS pathway. J Cell Physiol 2020; 235: 6582-91.
34. Weihong C, Bin C, Jianfeng Y. Transmembrane protein 126B protects against high fat diet (HFD)-induced renal injury by suppressing dyslipidemia via inhibition of ROS. Biochem Biophys Res Commun 2019; 509: 40-7.
35. Wu Y, Xia ZY, Dou J, et al. Protective effect of ginsenoside Rb1 against myocardial ischemia/reperfusion injury in streptozotocin-induced diabetic rats. Mol Biol Rep 2011; 38: 4327-35.
36. Kosuru R, Kandula V, Rai U, Prakash S, Xia Z, Singh S. Pterostilbene decreases cardiac oxidative stress and inflammation via activation of AMPK/Nrf2/HO-1 pathway in fructose-fed diabetic rats. Cardiovasc Drugs Ther 2018; 32: 147-63.
37. Ko JR, Seo DY, Park SH, et al. Aerobic exercise training decreases cereblon and increases AMPK signaling in the skeletal muscle of STZ-induced diabetic rats. Biochem Biophys Res Commun 2018; 501: 448-53.
38. Sun X, Song M, Wang H, et al. TRB3 gene silencing activates AMPK in adipose tissue with beneficial metabolic effects in obese and diabetic rats. Biochem Biophys Res Commun 2017; 488: 22-8.
39. Shih AY, Johnson DA, Wong G, et al. Coordinate regulation of glutathione biosynthesis and release by Nrf2-expressing glia potently protects neurons from oxidative stress. J Neurosci 2003; 23: 3394-406.
40. Tkachev VO, Menshchikova EB, Zenkov NK. Mechanism of the Nrf2/Keap1/ARE signaling system. Biochemistry (Mosc) 2011; 76: 407-22.
41. Cosso L, Maineri EP, Traverso N, et al. Induction of heme oxygenase 1 in liver of spontaneously diabetic rats. Free Radic Res 2001; 34: 189-91.
42. Kong HL, Li ZQ, Zhao YJ, et al. Ginsenoside Rb1 protects cardiomyocytes against CoCl2-induced apoptosis in neonatal rats by inhibiting mitochondria permeability transition pore opening. Acta Pharmacol Sin 2010; 31: 687-95.
43. Yu HT, Zhen J, Pang B, Gu JN, Wu SS. Ginsenoside Rg1 ameliorates oxidative stress and myocardial apoptosis in streptozotocin-induced diabetic rats. J Zhejiang Univ Sci B 2015; 16: 344-54.
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