Abstract
ABSTRACTHepatopulmonary syndrome (HPS) is a triad of advanced liver disease, intrapulmonary vasodilatation and arterial hypoxemia. Increasing evidence shows that HPS is associated with pulmonary microvascular hyperplasia. The aim of this work was to investigate the underlying mechanism of miR-145 in regulating the proliferation of pulmonary microvascular endothelial cells (PMVECs) and angiogenesis in HPS via plasminogen activator inhibitor-1 (PAI-1). To test this, morphology score and number of pulmonary microvascular were assessed in lung tissues from rats with HPS by Hematoxylin and Eosin (H&E) staining. Expression levels of PAI-1 were assessed in lung tissues from HPS rats, as well as in PMVECs treated with HPS rat serum. We also selected the putative microRNA binding site on PAI-1 by bioinformatics analysis. Then, miR145-3p and miR145-5p expression levels in the lungs and PMVECs of rats were detected by qRT-PCR because miR145-5p is a microRNA binding site on PAI-1. In addition, the effects of miR-145-5p regulation on PAI-1 were examined by upregulation and downregulation of miR-145-5p and specific lentivirus transfection was used to overexpress and knockdown PAI-1 to assess PAI-1 function on PMVECs proliferation. Our data showed that levels of PAI-1 expression in lung tissue of rats increased significantly when rats were treated with common bile duct ligation. We found that levels of miR-145-5p were frequently downregulated in HPS tissues and cell lines, and overexpression of miR-145-5p dramatically inhibited PMVECs proliferation. We further verified PAI-1 as a novel and direct target of miR-145-5p in HPS. MiR-145-5p inhibits PAI-1 synthesis and the expression changes of PAI-1 directly affect the proliferation of PMVECs. We concluded that miR-145-5p negatively regulates PMVEC proliferation through PAI-1 expression. In addition, overexpression of miR-145-5p may prove beneficial as a therapeutic strategy for HPS treatment.
Highlights
Hepatopulmonary syndrome (HPS) is a refractory disease with high morbidity and mortality characterized by advanced liver disease, hypoxemia and intrapulmonary vascular dilatation (IPVD) (Kammoun et al, 2007)
Significant pulmonary microvascular hyperplasia was found in lung tissue of HPS rats First, an HPS rat model was constructed using common bile duct ligation (CBDL)
The level of PaO2 in CBDL rats was significantly decreased (Fig. 1D). These results show that arterial oxygenation was impaired in the setting of pulmonary microvascular hyperplasia
Summary
Hepatopulmonary syndrome (HPS) is a refractory disease with high morbidity and mortality characterized by advanced liver disease, hypoxemia and intrapulmonary vascular dilatation (IPVD) (Kammoun et al, 2007). Multiple cytokines released by a diseased liver result in the activation and upregulation of signal proteins from multiple signaling pathways, such as TGF-β/Smad, Annexin A1/ A2, PI3K-Akt and PKC/ERK, leading to myogenic differentiation and proliferation of pulmonary microvascular endothelial cells (PMVECs) (Liu et al, 2017, 2015; Yi et al, 2013). These changes are the main pathophysiological changes that occur in IPVD and result in pulmonary microvascular pathological hyperplasia and expansion (He et al, 2017). The mechanism of alveolar capillary angiogenesis in HPS is incompletely understood
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