Glucose-regulated protein 78 may play a crucial role in promoting the pulmonary microvascular remodeling in a rat model of hepatopulmonary syndrome

Huiying Zhang, Minli Lv, Zhongfu Zhao, Jiantao Jia, Lili Zhang, Peng Xiao, Limin Wang, Chen Li, Jingquan Ji, Xiaoxia Tian, Xujiong Li, Yimin Fan, Lina Lai, Yan Liu, Baohong Li, Cuiying Zhang, Mingshe Liu, Jianhong Guo, Dewu Han, Cheng Ji

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Abstract

Objective: This study is to investigate the role of glucose-regulated protein 78 (GRP78) in the pulmonary microvascular remodeling during hepatopulmonary syndrome (HPS) development. Methods: The rat models with liver cirrhosis and HPS were induced by multiple pathogenic factors for 4 to 8. wk. The concentrations of alanine transferase (ALT) and endotoxin in plasma were detected in the models, followed by the detection of GRP78 expression. RT-PCR, quantitative real-time PCR and Western blotting were employed to assess the mRNA and protein expression levels of vascular endothelial growth factor (VEGF), respectively. Immunohistochemistry staining was used to examine the expression of a specific vascular marker, factor VIII-related antigen (FVIII-RAg), and several cell proliferation- and apoptosis-related proteins, including CHOP/GADD153, caspase-12, Bcl-2 and nuclear factor (NF)-κB. Results: The levels of endotoxin and ALT in plasma were gradually increased as the disease progressed, so did GRP78, which were in a positive correlation. The expression levels of VEGF (both mRNA and protein) and FVIII-RAg were significantly elevated in the HPS models, indicating active angiogenesis, which was also positively correlated with GRP78 expression. Furthermore, the expression levels of the pro-apoptotic proteins of CHOP/GADD153 and caspase-12 were dramatically decreased, while the anti-apoptotic proteins of Bcl-2 and NF-κB were significantly elevated, in the HPS models. There were also close correlation between these proteins and GRP78. Conclusions: Over-expression of GRP78 in lungs may be the critical pathogenic factor for HPS. Through promoting cell proliferation and survival and inhibiting apoptosis, GRP78 may promote the pulmonary microvascular remodeling in HPS pathogenesis. Our results provide a potential therapeutic target for clinical prevention and treatment for HPS and related complications.

Original languageEnglish
Pages (from-to)156-162
Number of pages7
JournalGene
Volume545
Issue number1
DOIs
Publication statusPublished - Jul 15 2014

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Keywords

  • Endotoxin
  • Glucose-regulated protein 78
  • Hepatopulmonary syndrome
  • Liver cirrhosis
  • Pulmonary microvascular remodeling

ASJC Scopus subject areas

  • Genetics

Cite this

Zhang, H., Lv, M., Zhao, Z., Jia, J., Zhang, L., Xiao, P., Wang, L., Li, C., Ji, J., Tian, X., Li, X., Fan, Y., Lai, L., Liu, Y., Li, B., Zhang, C., Liu, M., Guo, J., Han, D., & Ji, C. (2014). Glucose-regulated protein 78 may play a crucial role in promoting the pulmonary microvascular remodeling in a rat model of hepatopulmonary syndrome. Gene, 545(1), 156-162. https://doi.org/10.1016/j.gene.2014.04.041