Journal of Ginseng Research

The Korean Society of Ginseng (고려인삼학회)
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Ginsenoside Rg1 alleviates vascular remodeling in hypoxia-induced pulmonary hypertension mice through the calpain-1/STAT3 signaling pathway

  • Chenyang Ran (The Key Laboratory of Cardiovascular and Cerebrovascular Drug Research of Liaoning Province, Jinzhou Medical University) ;
  • Meili Lu (The Key Laboratory of Cardiovascular and Cerebrovascular Drug Research of Liaoning Province, Jinzhou Medical University) ;
  • Fang Zhao (Institute of Innovation and Applied Research in Chinese Medicine and Department of Rheumatology of the First Hospital, Hunan University of Chinese Medicine) ;
  • Yi Hao (The Key Laboratory of Cardiovascular and Cerebrovascular Drug Research of Liaoning Province, Jinzhou Medical University) ;
  • Xinyu Guo (The Key Laboratory of Cardiovascular and Cerebrovascular Drug Research of Liaoning Province, Jinzhou Medical University) ;
  • Yunhan Li (The Key Laboratory of Cardiovascular and Cerebrovascular Drug Research of Liaoning Province, Jinzhou Medical University) ;
  • Yuhong Su (The College of Food and Health of Liaoning Province, Jinzhou Medical University) ;
  • Hongxin Wang (The Key Laboratory of Cardiovascular and Cerebrovascular Drug Research of Liaoning Province, Jinzhou Medical University)
  • Received : 2023.07.05
  • Accepted : 2024.03.04
  • Published : 2024.07.01
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Abstract

Background: Hypoxic pulmonary hypertension (HPH) is the main pathological change in vascular remodeling, a complex cardiopulmonary disease caused by hypoxia. Some research results have shown that ginsenoside Rg1 (Rg1) can improve vascular remodeling, but the effect and mechanism of Rg1 on hypoxia-induced pulmonary hypertension are not clear. The purpose of this study was to discuss the potential mechanism of action of Rg1 on HPH. Methods: C57BL/6 mice, calpain-1 knockout mice and Pulmonary artery smooth muscle cells (PASMCs) were exposed to a low oxygen environment with or without different treatments. The effect of Rg1 and calpain-1 silencing on inflammation, fibrosis, proliferation and the protein expression levels of calpain-1, STAT3 and p-STAT3 were determined at the animal and cellular levels. Results: At the mouse and cellular levels, hypoxia promotes inflammation, fibrosis, and cell proliferation, and the expression of calpain-1 and p-STAT3 is also increased. Ginsenoside Rg1 administration and calpain-1 knockdown, MDL-28170, and HY-13818 treatment showed protective effects on hypoxia-induced inflammation, fibrosis, and cell proliferation, which may be associated with the downregulation of calpain-1 and p-STAT3 expression in mice and cells. In addition, overexpression of calpain 1 increased p-STAT3 expression, accelerating the onset of inflammation, fibrosis and cell proliferation in hypoxic PASMCs. Conclusion: Ginsenoside Rg1 may ameliorate hypoxia-induced pulmonary vascular remodeling by suppressing the calpain-1/STAT3 signaling pathway.

Keywords

Acknowledgement

The authors acknowledge lab mates for them help or advice during experiments.

References

  1. Ye Y, Xu Q, Wuren T. Inflammation and immunity in the pathogenesis of hypoxic pulmonary hypertension. Front Immunol 2023;14:1162556. 
  2. Barman SA, et al. Galectin-3 is expressed in vascular smooth muscle cells and promotes pulmonary hypertension through changes in proliferation, apoptosis, and fibrosis. Am J Physiol Lung Cell Mol Physiol 2019;316(5):L784-97. 
  3. Remes A, et al. Adeno-associated virus-mediated gene transfer of inducible nitric oxide synthase to an animal model of pulmonary hypertension. Hum Gene Ther 2022;33(17-18):959-67. 
  4. Rowan SC, et al. Hypoxic pulmonary hypertension in chronic lung diseases: novel vasoconstrictor pathways. Lancet Respir Med 2016;4(3):225-36. 
  5. Rawlings JS, Rosler KM, Harrison DA. The JAK/STAT signaling pathway. J Cell Sci 2004;117(Pt 8):1281-3. 
  6. Greenhill CJ, et al. IL-6 trans-signaling modulates TLR4-dependent inflammatory responses via STAT3. J Immunol 2011;186(2):1199-208. 
  7. Groner B, Lucks P, Borghouts C. The function of Stat3 in tumor cells and their microenvironment. Semin Cell Dev Biol 2008;19(4):341-50. 
  8. Pulivendala G, Bale S, Godugu C. Honokiol: a polyphenol neolignan ameliorates pulmonary fibrosis by inhibiting TGF-beta/Smad signaling, matrix proteins and IL-6/CD44/STAT3 axis both in vitro and in vivo. Toxicol Appl Pharmacol 2020;391:114913. 
  9. Zhang L, et al. Blockade of JAK2 protects mice against hypoxia-induced pulmonary arterial hypertension by repressing pulmonary arterial smooth muscle cell proliferation. Cell Prolif 2020;53(2):e12742. 
  10. Wu X, et al. Enriched housing promotes post-stroke neurogenesis through calpain 1-STAT3/HIF-1alpha/VEGF signaling. Brain Res Bull 2018;139:133-43. 
  11. Yu L, et al. Calpain inhibitor I attenuates atherosclerosis and inflammation in atherosclerotic rats through eNOS/NO/NF-kappaB pathway. Can J Physiol Pharmacol 2018;96(1):60-7. 
  12. Tabata C, Tabata R, Nakano T. The calpain inhibitor calpeptin prevents bleomycin-induced pulmonary fibrosis in mice. Clin Exp Immunol 2010;162(3):560-7. 
  13. Deng H, et al. Calpain-1 mediates vascular remodelling and fibrosis via HIF-1alpha in hypoxia-induced pulmonary hypertension. J Cell Mol Med 2022;26(10):2819-30. 
  14. Li FZ, et al. Crosstalk between calpain activation and TGF-beta1 augments collagen-I synthesis in pulmonary fibrosis. Biochim Biophys Acta 2015;1852(9):1796-804. 
  15. Zhu GX, et al. Ginsenosides in vascular remodeling: cellular and molecular mechanisms of their therapeutic action. Pharmacol Res 2021;169:105647. 
  16. Li CY, et al. The effects and mechanism of ginsenoside Rg1 on myocardial remodeling in an animal model of chronic thromboembolic pulmonary hypertension. Eur J Med Res 2013;18(1):16. 
  17. Zhao F, Lu M, Wang H. Ginsenoside Rg1 ameliorates chronic intermittent hypoxia-induced vascular endothelial dysfunction by suppressing the formation of mitochondrial reactive oxygen species through the calpain-1 pathway. J Ginseng Res 2023;47(1):144-54. 
  18. Tang BL, et al. Ginsenoside Rg1 ameliorates hypoxia-induced pulmonary arterial hypertension by inhibiting endothelial-to-mesenchymal transition and inflammation by regulating CCN1. Biomed Pharmacother 2023;164:114920. 
  19. Dahal BK, et al. Role of epidermal growth factor inhibition in experimental pulmonary hypertension. Am J Respir Crit Care Med 2010;181(2):158-67. 
  20. Naeije R, Richter MJ, Rubin LJ. The physiological basis of pulmonary arterial hypertension. Eur Respir J 2022;59(6). 
  21. Dodson MW, Brown LM, Elliott CG. Pulmonary arterial hypertension. Heart Fail Clin 2018;14(3):255-69. 
  22. Park JH, et al. 2020 KSC/KATRD guideline for the diagnosis and treatment of pulmonary hypertension: executive summary. Tuberc Respir Dis 2022;85(1):1-10. 
  23. Sakao S, et al. Determinants of an elevated pulmonary arterial pressure in patients with pulmonary arterial hypertension. Respir Res 2015;16(1):84. 
  24. Chang YT, et al. Perlecan heparan sulfate deficiency impairs pulmonary vascular development and attenuates hypoxic pulmonary hypertension. Cardiovasc Res 2015;107(1):20-31. 
  25. Morrell NW, et al. Cellular and molecular basis of pulmonary arterial hypertension. J Am Coll Cardiol 2009;54(1 Suppl):S20-31. 
  26. Pugliese SC, et al. The role of inflammation in hypoxic pulmonary hypertension: from cellular mechanisms to clinical phenotypes. Am J Physiol Lung Cell Mol Physiol 2015;308(3):L229-52. 
  27. Rabinovitch M, et al. Inflammation and immunity in the pathogenesis of pulmonary arterial hypertension. Circ Res 2014;115(1):165-75.
  28. Savai R, et al. Immune and inflammatory cell involvement in the pathology of idiopathic pulmonary arterial hypertension. Am J Respir Crit Care Med 2012;186(9):897-908. 
  29. Levy DE, Darnell JJ. Stats: transcriptional control and biological impact. Nat Rev Mol Cell Biol 2002;3(9):651-62. 
  30. You L, et al. The role of STAT3 in autophagy. Autophagy 2015;11(5):729-39. 
  31. Zhang L, et al. Blockade of JAK2 protects mice against hypoxia-induced pulmonary arterial hypertension by repressing pulmonary arterial smooth muscle cell proliferation. Cell Prolif 2020;53(2):e12742. 
  32. Zhang L, et al. Blockade of JAK2 protects mice against hypoxia-induced pulmonary arterial hypertension by repressing pulmonary arterial smooth muscle cell proliferation. Cell Prolif 2020;53(2):e12742. 
  33. Zhang M, Wang G, Peng T. Calpain-mediated mitochondrial damage: an emerging mechanism contributing to cardiac disease. Cells 2021;10(8). 
  34. Zhao F, Lu M, Wang H. Ginsenoside Rg1 ameliorates chronic intermittent hypoxia-induced vascular endothelial dysfunction by suppressing the formation of mitochondrial reactive oxygen species through the calpain-1 pathway. J Ginseng Res 2023;47(1):144-54. 
  35. Meng Y, et al. Astragaloside IV alleviates brain injury induced by hypoxia via the calpain-1 signaling pathway. Neural Plast 2022;2022:6509981. 
  36. Zhao F, et al. Protective effect of Astragaloside IV on chronic intermittent hypoxia-induced vascular endothelial dysfunction through the calpain-1/SIRT1/AMPK signaling pathway. Front Pharmacol 2022;13:920977. 
  37. Deng H, et al. Calpain-1 mediates vascular remodelling and fibrosis via HIF-1alpha in hypoxia-induced pulmonary hypertension. J Cell Mol Med 2022;26(10):2819-30. 
  38. Wu X, et al. Enriched housing promotes post-stroke neurogenesis through calpain 1-STAT3/HIF-1alpha/VEGF signaling. Brain Res Bull 2018;139:133-43.