Long-term liver deportalisation in stable and time prolonged prehepatic portal hypertension model affects expression of hypoxia, angiogenesis, apoptosis, and autophagy markers in the young rats’ liver

Oleg Godik

doi:10.32345/USMYJ.3(149).2024.66-74

Oleg Godik 1 Bogomolets National Medical University, Kyiv, Ukraine; 2 National Specialized Children’s Hospital “Ohmatdyt”, Kyiv, Ukraine https://orcid.org/0000-0002-1084-9484

DOI: https://doi.org/10.32345/USMYJ.3(149).2024.66-74

Keywords: Angiogenesis; Apoptosis; Autophagy; Hypertension; Hypoxia; Rats.

Abstract

prehepatic portal hypertension in children cause severe and life-threatening complications, that highlights the need in in-depth investigations of pathogenetic mechanisms, which contribute to prehepatic portal hypertension-associated liver pathology. In developed stable experimental prehepatic portal hypertension model in adolescent rat males we aimed to assess the expression levels of the key molecular markers of hypoxia, angiogenesis, autophagy, and apoptosis in the liver tissue after 6-month deportalization. Partial portal vein ligation was performed in 4-week old male rats. After 6-months tissue samples from PHP-model, sham operated and control animals were studied by western blot to identify protein levels of markers related to prehepatic portal hypertension -induced liver injury. Partial portal vein occlusion upregulated hypoxia inducible factor -1α (by 4.67 folds vs. control, p<0.001) and vascular endothelial growth factor protein expression levels (by 2.33 folds vs. control, p<0.001) suggesting chronic hypoxia development. Abnormally high levels of angiostatin isoforms were found (by 9.88 folds vs. control, p<0.001) to signify angiogenesis dysregulation. Significant caspase-3 (23.4-fold increase vs. control, p<0.001) overexpression is executive phase of apoptotic cell death evidence. Dramatic LC3 level expression indicates existence of crosstalk between autophagy and apoptosis that contribute to fibrotic changes. Hypoxia-induced events, impaired angiogenesis regulation, enhanced autophagy and apoptosis are contributing factors of prehepatic portal hypertension -induced liver injury. A better understanding of subtle molecular mechanisms of this pathology may pave the way for innovative treatment options.

References

Abraldes, J. G., Pasarín, M., & García-Pagán, J. C. (2006). Animal models of portal hypertension. World journal of gastroenterology, 12(41), 6577–6584. https://doi.org/10.3748/wjg.v12.i41.6577

de Ville de Goyet, J., D'Ambrosio, G., & Grimaldi, C. (2012). Surgical management of portal hypertension in children. Seminars in pediatric surgery, 21(3), 219–232. https://doi.org/10.1053/j.sempedsurg.2012.05.005

Drixler, T. A., Vogten, M. J., Ritchie, E. D., van Vroonhoven, T. J., Gebbink, M. F., Voest, E. E., & Borel Rinkes, I. H. (2002). Liver regeneration is an angiogenesis- associated phenomenon. Annals of surgery, 236(6), 703–712. https://doi.org/10.1097/00000658-200212000-00002

Fernández, M., Semela, D., Bruix, J., Colle, I., Pinzani, M., & Bosch, J. (2009). Angiogenesis in liver disease. Journal of hepatology, 50(3), 604–620. https://doi.org/10.1016/j.jhep.2008.12.011

Gao, Z. Q., Han, Y., Li, L., & Ding, H. G. (2020). Pharmacological management of portal hypertension: current status and future. Chinese medical journal, 133(19), 2362–2364. https://doi.org/10.1097/CM9.0000000000001004

Gana, J. C., Serrano, C. A., & Ling, S. C. (2016). Angiogenesis and portal-systemic collaterals in portal hypertension. Annals of hepatology, 15(3), 303–313. https://doi.org/10.5604/16652681.1198799

Godik, O., Zhumik, D., Diehtiarova, D., Levytskii, A., & Lapikova-Bryhinska, T. (2023). A model of prehepatic portal hypertension in rats. The Ukrainian Scientific Medical Youth Journal, 139(2), 17-24. DOI: 0.32345/USMYJ.2(139).2023.17-24

Jung, S., Jeong, H., & Yu, S. W. (2020). Autophagy as a decisive process for cell death. Experimental & molecular medicine, 52(6), 921–930. https://doi.org/10.1038/s12276-020-0455-4

Lautz, T. B., Sundaram, S. S., Whitington, P. F., Keys, L., & Superina, R. A. (2009). Growth impairment in children with extrahepatic portal vein obstruction is improved by mesenterico-left portal vein bypass. Journal of pediatric surgery, 44(11), 2067–2070. https://doi.org/10.1016/j.jpedsurg.2009.05.016

Kouroumalis, E., Voumvouraki, A., Augoustaki, A., & Samonakis, D. N. (2021). Autophagy in liver diseases. World journal of hepatology, 13(1), 6–65. https://doi.org/10.4254/wjh.v13.i1.6

Niu, G., & Chen, X. (2010). Vascular endothelial growth factor as an anti-angiogenic target for cancer therapy. Current drug targets, 11(8), 1000–1017. https://doi.org/10.2174/138945010791591395

Quintero-Fabián, S., Arreola, R., Becerril-Villanueva, E., Torres-Romero, J. C., Arana-Argáez, V., Lara-Riegos, J., Ramírez-Camacho, M. A., & Alvarez-Sánchez, M. E. (2019). Role of Matrix Metalloproteinases in Angiogenesis and Cancer. Frontiers in oncology, 9, 1370. https://doi.org/10.3389/fonc.2019.01370

Ruan, Q., Zhao, C., Ye, Z., Ruan, J., Xie, Q., & Xie, W. (2015). Effect and possible mechanism of monocyte-derived VEGF on monocyte-endothelial cellular adhesion after electrical burns. Burns : journal of the International Society for Burn Injuries, 41(4), 825–832. https://doi.org/10.1016/j.burns.2014.10.030

Schettino, G. C., Fagundes, E. D., Roquete, M. L., Ferreira, A. R., & Penna, F. J. (2006). Portal vein thrombosis in children and adolescents. Jornal de pediatria, 82(3), 171–178. https://doi.org/10.2223/JPED.1484

Schläfli, A. M., Adams, O., Galván, J. A., Gugger, M., Savic, S., Bubendorf, L., Schmid, R. A., Becker, K. F., Tschan, M. P., Langer, R., & Berezowska, S. (2016). Prognostic value of the autophagy markers LC3 and p62/SQSTM1 in early-stage non-small cell lung cancer. Oncotarget, 7(26), 39544–39555. https://doi.org/10.18632/oncotarget.9647

Schmitz, V., Raskopf, E., Gonzalez-Carmona, M. A., Vogt, A., Rabe, C., Leifeld, L., Kornek, M., Sauerbruch, T., & Caselmann, W. H. (2007). Plasminogen fragment K1-5 improves survival in a murine hepatocellular carcinoma model. Gut, 56(2), 271–278. https://doi.org/10.1136/gut.2005.088583

Soff G. A. (2000). Angiostatin and angiostatin-related proteins. Cancer metastasis reviews, 19(1-2), 97–107. https://doi.org/10.1023/a:1026525121027

Stoscheck C. M. (1990). Quantitation of protein. Methods in enzymology, 182, 50–68. https://doi.org/10.1016/0076-6879(90)82008-p

Vogten J.M., Drixler T.A., Te Velde E.A., Schipper M.E., Van Vroonhoven T.J., Voest E.E., Borel Rinkes I.H. Angiostatin Inhibits Experimental Liver Fibrosis in Mice. Int. J. Colorectal. Dis. 2004;19:387–394. doi: 10.1007/s00384-003-0562-4.

Wen, Z., Zhang, J. Z., Xia, H. M., Yang, C. X., & Chen, Y. J. (2009). Stability of a rat model of prehepatic portal hypertension caused by partial ligation of the portal vein. World journal of gastroenterology, 15(32), 4049–4054. https://doi.org/10.3748/wjg.15.4049

Ye, H. L., Zhang, J. W., Chen, X. Z., Wu, P. B., Chen, L., & Zhang, G. (2020). Ursodeoxycholic acid alleviates experimental liver fibrosis involving inhibition of autophagy. Life sciences, 242, 117175. https://doi.org/10.1016/j.lfs.2019.117175

Zhou, J. C., Wang, J. L., Ren, H. Z., & Shi, X. L. (2022). Autophagy plays a double-edged sword role in liver diseases. Journal of physiology and biochemistry, 78(1), 9–17. https://doi.org/10.1007/s13105-021-00844-7