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

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 correlations 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.

Hepatopulmonary syndrome and portopulmonary hypertension: recent knowledge in pathogenesis and overview of clinical assessment

“…These data showed increased expression levels of VEGF, factor VIII-related antigen and GRP78 and decreased levels of anti-apoptotic proteins (52). These results led to the assumption that GRP78 may play a role in inducing pulmonary vascular remodelling in HPS through promoting cell proliferation and survival and inhibiting apoptosis (52). Figure 2 summarizes the current knowledge on the pathogenesis and pathophysiology of HPS based on rat studies.…”

“…A recent study investigated the role of glucose‐regulated protein 78 (GRP78) in the pulmonary microvascular remodelling during experimental HPS development . These data showed increased expression levels of VEGF, factor VIII‐related antigen and GRP78 and decreased levels of anti‐apoptotic proteins .…”

“…A recent study investigated the role of glucose‐regulated protein 78 (GRP78) in the pulmonary microvascular remodelling during experimental HPS development . These data showed increased expression levels of VEGF, factor VIII‐related antigen and GRP78 and decreased levels of anti‐apoptotic proteins . These results led to the assumption that GRP78 may play a role in inducing pulmonary vascular remodelling in HPS through promoting cell proliferation and survival and inhibiting apoptosis .…”

Nanoparticles inhibit cancer cell invasion and enhance antitumor efficiency by targeted drug delivery via cell surface-related GRP78

“…17 Many data have shown that GRP78 is overexpressed on the cell surface in many human cancers such as melanoma, lung cancer, breast cancer, and hepatocellular carcinoma. [18][19][20] Cell surface GRP78 is involved in the regulation …”

Liver epigenome changes in patients with hepatopulmonary syndrome: A pilot study

“…First, pulmonary angiogenesis and vascular remodeling are considered key pathogenic features of HPS [ 3 , 30 ], mostly involving the activation of vascular endothelial growth factor (VEGF)-dependent pathways [ 14 , 31 – 33 ]. In this context, it is of note that some of the top differentially methylated genes identified in patients with HPS ( Table 2 ) were also related to angiogenesis, including VAV3 [ 34 ], PAX 8 [ 35 ], K-RAS [ 36 ] and LAMA2 [ 37 ].…”