Abstract
Hepatopulmonary syndrome (HPS) is a serious complication of advanced liver disease, which markedly increases mortality. Pulmonary vascular remodelling (PVR) induced by circulating mediators plays an important role in the pathogenesis of HPS, while the underlying mechanism remains undefined. In the present study, we reported that endothelin-1 (ET-1) is up-regulated and annexin A1(ANXA1) is down-regulated in HPS rat, and ET-1 decreases the ANXA1 expression in a dose-dependent manner in rat pulmonary arterial smooth muscle cells (PASMCs). Then, we showed that ANXA1 can decrease nuclear p-ERK1/2 accumulation and decrease the cyclin D1 expression, thus resulting in the subsequent inhibition of PASMCs proliferation. As previously reported, we confirmed that ET-1 decreases the ANXA1 protein levels by the carbonylation and degradation of ANXA1. In conclusion, our research links the signaling cascade of ET1-ANXA1-cell proliferation to a potential therapeutic strategy for blocking IPS-associated PVR.
Highlights
Liver plays an important role in homoeostasis, and chronic liver diseases, such as cirrhosis and portal hypertension, often lead to the alterations of vasculature in multiple organs[1]
Liver cirrhosis and other chronic liver dysfunction can lead to reduced hepatic clearance or enhanced production of circulating mediators, including growth factors and cytokines, both of which are the major contributors to Pulmonary vascular remodelling (PVR)
Our previous study indicated that inflammation and proliferation of pulmonary artery smooth muscle cells (PASMCs) may play an important role in this process[21]
Summary
Liver plays an important role in homoeostasis, and chronic liver diseases, such as cirrhosis and portal hypertension, often lead to the alterations of vasculature in multiple organs[1]. Hepatopulmonary syndrome(HPS), an advanced liver disease causing lung vascular disorder, has drawn more and more attention in recent years because of it high mortality. HPS has three clinical characteristics: advanced chronic liver disease (CLD), intrapulmonary vasodilatation (IPVD), and arterial hypoxemia[2]. Orthotopic liver transplantation(OLT) is the only viable treatment option. As one of the major components of blood vessel wall, pulmonary artery smooth muscle cells (PASMCs) play an important role in maintaining vascular structure and functions. PASMCs are normally quiescent and seldom to proliferate (
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