Gypenosides alleviates MCT-induced pulmonary arterial hypertension in rats by targeting oxidative stress, inflammation, and apoptosis

Articles in Press

Document Type : Original Article

Authors

Department of Respiratory and Critical Care Medicine, The Second Hospital of Hebei Medical University, Shijiazhuang, 050000, China

10.22038/ijbms.2025.82437.17822

Abstract

Objective(s): Pulmonary arterial hypertension (PAH) is a severe heart-lung condition characterized by complex changes in the pulmonary vasculature, known as pulmonary vascular remodeling (PVR). Gypenosides (Gyp) possesses a range of pharmacological properties, including anti-inflammatory and anti-oxidant effects. This study aims to explore the impact of Gyp on pulmonary vascular remodeling, particularly in relation to its potential to counteract inflammation, oxidative stress, and apoptosis.
Materials and Methods: Twenty-four rats were randomly divided into four groups. MCT was administered via intraperitoneal injection at a 55 mg/kg dose to establish a PAH model. Gyp (150 mg/kg/day, Ig) was administered for 28 days, after which all lung tissues from the rats were isolated.
Results: The findings indicated that Gyp had a substantial positive impact on the hemodynamics of rats with PAH induced by MCT, including reductions in mean pulmonary artery pressure (mPAP) and right ventricular systolic pressure (RVSP). Additionally, it exhibited inhibitory effects on right ventricular hypertrophy and pulmonary vascular remodeling in these PAH-afflicted rats. MCT elevated the concentration of MDA (P<0.01 in the lung) while reducing the levels of SOD and GSH-PX (P<0.0001). Furthermore, MCT enhanced the expression of IL-6, TNF-α, and IL-1β (P<0.0001), as well as the mRNA expression of NF-κB (P<0.001) and the Bcl2 level (P<0.0001), while it lowered the expression of Bax (P<0.0001). Conversely, Gyp treatment effectively mitigated all of these alterations.
Conclusion: This study represents the initial investigation showing that Gyp treatment attenuates PVR by inhibiting oxidative stress, inflammation, and apoptosis, providing a foundation for further research.

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References

1. Humbert M, Kovacs G, Hoeper MM, Badagliacca R, Berger RMF, Brida M, et al. 2022 ESC/ERS guidelines for the diagnosis and treatment of pulmonary hypertension. Eur Respir J 2023; 61: 2200879.
2. Kularatne M, Gerges C, Jevnikar M, Humbert M, Montani D. Updated clinical classification and hemodynamic definitions of pulmonary hypertension and its clinical implications. J Cardiovasc Dev Dis 2024; 11: 78-90.
3. Humbert M, Guignabert C, Bonnet S, Dorfmüller P, Klinger JR, Nicolls MR, et al. Pathology and pathobiology of pulmonary hypertension: state of the art and research perspectives. Eur Respir J 2019; 53: 1801887-1801901.
4. Liu Y, Tang BL, Lu ML, Wang HX. Astragaloside IV improves pulmonary arterial hypertension by increasing the expression of CCN1 and activating the ERK1/2 pathway. J Cell Mol Med 2023; 27: 622-633.
5. Wang RR, Yuan TY, Wang JM, Chen YC, Zhao JL, Li MT, et al. Immunity and inflammation in pulmonary arterial hypertension: From pathophysiology mechanisms to treatment perspective. Pharmacol Res 2022; 180: 106238.
6. Stenmark KR, Frid MG, Graham BB, Tuder RM. Dynamic and diverse changes in the functional properties of vascular smooth muscle cells in pulmonary hypertension. Cardiovasc Res 2018; 114: 551-564.
7. Zhao H, Song J, Li X, Xia Z, Wang Q, Fu J, et al. The role of immune cells and inflammation in pulmonary hypertension: Mechanisms and implications. Front Immunol 2024; 15: 1374506-1374515.
8. Huertas A, Tu L, Humbert M, Guignabert C. Chronic inflammation within the vascular wall in pulmonary arterial hypertension: more than a spectator. Cardiovasc Res 2020; 116: 885-893.
9. Farkas D, Alhussaini AA, Kraskauskas D, Kraskauskiene V, Cool CD, Nicolls MR, et al. Nuclear factor κB inhibition reduces lung vascular lumen obliteration in severe pulmonary hypertension in rats. Am J Respir Cell Mol Biol 2014; 51: 413-425.
10. Chai Y, Gu X, Zhang H, Xu X, Chen L. Phoenixin 20 ameliorates pulmonary arterial hypertension via inhibiting inflammation and oxidative stress. Aging (Albany NY) 2024; 16: 5027-5037.
11. Xie P, Luo HT, Pei WJ, Xiao MY, Li FF, Gu YL, et al. Saponins derived from gynostemma pentaphyllum regulate triglyceride and cholesterol metabolism and the mechanisms: A review. J Ethnopharmacol 2024; 319: 117186.
12. Huang YP, Wang YS, Liu YY, Jiang CH, Wang J, Jiang XY, et al. Chemical characterization and atherosclerosis alleviation effects of gypenosides from gynostemma pentaphyllum through ameliorating endothelial dysfunction via the PCSK9/LOX-1 pathway. J Agric Food Chem 2022; 70: 11944-11957.
13. Qi YS, Xie JB, Xie P, Duan Y, Ling YQ, Gu YL, et al. Uncovering the anti-NSCLC effects and mechanisms of gypenosides by metabolomics and network pharmacology analysis. J Ethnopharmacol 2021; 281: 114506.
14. Tu Q, Zhu Y, Yuan Y, Guo L, Liu L, Yao L, et al. Gypenosides inhibit inflammatory response and apoptosis of endothelial and epithelial cells in LPS-induced ALI: A study based on bioinformatic analysis and in vivo/vitro experiments. Drug Des Devel Ther 2021; 15: 289-303.
15. Zhu KN, Tian SS, Wang H, Tian YS, Gu GZ, Qiu YY, et al. [Study on effect of gypenosides on insulin sensitivity of rats with diabetes mellitus via regulating NF-κB signaling pathway]. Zhongguo Zhong Yao Za Zhi 2021; 46: 4488-4496.
16. Zhou T, Cao L, Du Y, Qin L, Lu Y, Zhang Q, et al. Gypenosides ameliorate high-fat diet-induced nonalcoholic fatty liver disease in mice by regulating lipid metabolism. PeerJ 2023; 11: e15225-15243.
17. Su C, Li N, Ren R, Wang Y, Su X, Lu F, et al. Progress in the medicinal value, bioactive compounds, and pharmacological activities of Gynostemma pentaphyllum. Molecules 2021; 26: 6249-6284.
18. Yu H, Shi L, Qi G, Zhao S, Gao Y, Li Y. Gypenoside protects cardiomyocytes against ischemia-reperfusion injury via the inhibition of mitogen-activated protein kinase mediated nuclear factor kappa B pathway in vitro and in vivo. Front Pharmacol 2016; 7: 148-159.
19. Alhasani RH, Biswas L, Tohari AM, Zhou X, Reilly J, He JF, et al. Gypenosides protect retinal pigment epithelium cells from oxidative stress. Food Chem Toxicol 2018; 112: 76-85.
20. Liu J, Fang G, Lan C, Qiu C, Yao L, Zhang Q, et al. Forsythoside B mitigates monocrotaline-induced pulmonary arterial hypertension via blocking the NF-κB signaling pathway to attenuate vascular remodeling. Drug Des Devel Ther 2024; 18: 767-780.
21. Sheng Y, Gong X, Zhao J, Liu Y, Yuan Y. Effects of crocin on CCL2/CCR2 inflammatory pathway in monocrotaline-induced pulmonary arterial hypertension rats. Am J Chin Med 2022; 50: 241-259.
22. Gao AR, Li S, Tan XC, Huang T, Dong HJ, Xue R, et al. Xinyang tablet attenuates chronic hypoxia-induced right ventricular remodeling via inhibiting cardiomyocytes apoptosis. Chin Med 2022; 17: 134-147.
23. Yang M, Zhang T. Genistein inhibits the release of proinflammatory substances from macrophages by suppressing potassium loss- and ROS-mediated caspase-1/gasdermin D pathway activation and pyroptotic cell lysis. Iran J Basic Med Sci 2024; 27: 1506-1514.
24. Aimaier S, Tao Y, Lei F, Yupeng Z, Wenhui S, Aikemu A, et al. Protective effects of the Terminalia bellirica tannin-induced Nrf2/HO-1 signaling pathway in rats with high-altitude pulmonary hypertension. BMC Complement Med Ther 2023; 23: 150-161.
25. Gomez-Arroyo JG, Farkas L, Alhussaini AA, Farkas D, Kraskauskas D, Voelkel NF, et al. The monocrotaline model of pulmonary hypertension in perspective. Am J Physiol Lung Cell Mol Physiol 2012; 302: L363-369.
26. Wu XH, Ma JL, Ding D, Ma YJ, Wei YP, Jing ZC. Experimental animal models of pulmonary hypertension: Development and challenges. Animal Model Exp Med 2022; 5: 207-216.
27. Chen Y, Ma P, Bo L, Lv Y, Zhou W, Zhou R. Isorhamnetin alleviates symptoms and inhibits oxidative stress levels in rats with pulmonary arterial hypertension. Iran J Basic Med Sci 2024; 27: 1616-1623.
28. Wang J, Wang L, Chen X, Liang ML, Wei DH, Cao W, et al. Cigarette smoke extract stimulates human pulmonary artery smooth muscle cell proliferation: Role of inflammation and oxidative stress. Iran J Basic Med Sci 2022; 25: 755-761.
29. Hu Y, Chi L, Kuebler WM, Goldenberg NM. Perivascular inflammation in pulmonary arterial hypertension. Cells 2020; 9: 2338-2363.
30. Yoo HHB, Marin FL. Treating inflammation associated with pulmonary hypertension: An overview of the literature. Int J Gen Med 2022; 15: 1075-1083.
31. Hong J, Arneson D, Umar S, Ruffenach G, Cunningham CM, Ahn IS, et al. Single-cell study of two rat models of pulmonary arterial hypertension reveals connections to human pathobiology and drug repositioning. Am J Respir Crit Care Med 2021; 203: 1006-1022.
32. Soon E, Holmes AM, Treacy CM, Doughty NJ, Southgate L, Machado RD, et al. Elevated levels of inflammatory cytokines predict survival in idiopathic and familial pulmonary arterial hypertension. Circulation 2010; 122: 920-927.
33. Savai R, Pullamsetti SS, Kolbe J, Bieniek E, Voswinckel R, Fink L, et al. Immune and inflammatory cell involvement in the pathology of idiopathic pulmonary arterial hypertension. Am J Respir Crit Care Med 2012; 186: 897-908.
34. Hosokawa S, Haraguchi G, Sasaki A, Arai H, Muto S, Itai A, et al. Pathophysiological roles of nuclear factor kappaB (NF-kB) in pulmonary arterial hypertension: Effects of synthetic selective NF-kB inhibitor IMD-0354. Cardiovasc Res 2013; 99: 35-43.
35. Yao W, Fan M, Qian H, Li Y, Wang L. Quinoa polyphenol extract alleviates non-alcoholic fatty liver disease via inhibiting lipid accumulation, inflammation and oxidative stress. Nutrients 2024; 16: 2276-2292.
36. Kim SJ, Jo YJ, Jeong SH, Kim YH, Hee Han J. An investigation of antioxidative and anti-inflammatory effects of Taraxacum coreanum (white dandelion) in lactating Holstein dairy cows. J Adv Vet Anim Res 2024; 11: 330-338.
37. Mokhtari T, Lu M, El-Kenawy AE. Potential anxiolytic and antidepressant-like effects of luteolin in a chronic constriction injury rat model of neuropathic pain: Role of oxidative stress, neurotrophins, and inflammatory factors. Int Immunopharmacol 2023; 122: 110520.
38. Jin H, Jiao Y, Guo L, Ma Y, Zhao R, Li X, et al. Astragaloside IV blocks monocrotalineinduced pulmonary arterial hypertension by improving inflammation and pulmonary artery remodeling. Int J Mol Med 2021; 47: 595-606.
39. Li X, Tan J, Wan J, Cheng B, Wang YH, Dai A. Cell death in pulmonary arterial hypertension. Int J Med Sci 2024; 21: 1840-1851.
40. Lin J, Chen R, Liao H, Zhang Y, Zheng Z, Hong C. Mechanisms of cordycepin in the treatment of pulmonary arterial hypertension in rats based on metabonomics and transcriptomics. Sci Rep 2024; 14: 12431-12449.
Iranian Journal of Basic Medical Sciences

Articles in Press, Accepted Manuscript
Available Online from 30 April 2025

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