Abstract
Hypoxia is a common environmental stress factor and is associated with fibrogenesis. Matrix metalloproteinase-2 (MMP-2), produced by hepatic stellate cells (HSCs), plays an important role in liver fibrogenesis. However, inconsistent results have been reported on the impact of hypoxia on MMP-2 expression and activity in HSCs. We speculated that cell–cell interaction is involved in the regulation of MMP-2 expression and activity at low oxygen level in vivo. Therefore, in this report we investigated the mechanism by which hypoxic hepatocytes regulates MMP-2 expression in HSCs. Our results showed that the conditioned medium from hypoxia-treated rat hepatocytes strongly induced the expression of MMP-2 mRNA and protein in rat HSC-T6 cells. Reduced glutathione neutralized ROS released from hypoxic hepatocytes, leading to reduced MMP-2 expression in HSC-T6 cells. In addition, phospho-IκB-α protein level was increased in HSC-T6 cells treated with hypoxia conditioned medium, and NF-κB signaling inhibitor inhibited MMP-2 expression in HSC-T6 cells. Taken together, our data suggest that ROS is an important factor released by hypoxic hepatocytes to regulate MMP-2 expression in HSCs, and NF-κB signaling is crucially involved in ROS-induced MMP-2 expression in HSCs. Our findings suggest that strategies aimed at antagonizing the generation of ROS in hypoxic hepatocytes and inhibiting NF-κB signaling in HSCs may represent novel therapeutic options for liver fibrosis.
Highlights
It is estimated that over 100 million people suffer from liver fibrosis in the world
Our results suggest that reactive oxygen species (ROS) is an important factor released by hypoxic hepatocyte to regulate Matrix metalloproteinase-2 (MMP-2) expression in hepatic stellate cells (HSCs) and NF-κB signaling is crucially involved in these processes
To investigate whether hypoxic hepatocytes affect the expression of matrix metalloproteinase (MMP)-2 mRNA in HSC-T6 cells, we measured MMP-2 mRNA level in rat HSC-T6 cells cultured in hepatocyte-conditioned medium for 6, 12 and 24 h, respectively
Summary
It is estimated that over 100 million people suffer from liver fibrosis in the world. As the main complication of chronic liver damage, liver fibrosis is a wound healing process characterized by the accumulation of extracellular matrix (ECM) proteins in the liver. Liver fibrosis is caused by a variety of etiologic agents, including chronic viral hepatitis, alcohol toxicity, autoimmune disease, and hereditary metabolic disorders, it is generally accepted that a central pathologic mechanism underlying liver fibrosis is the generation and proliferation of smooth muscle α-actin (α-SMA)-positive myofibroblasts of periportal and perisinusoidal origin that arise as a consequence of the activation of hepatic stellate cells (HSCs) [1,2,3,4]. The activation of HSCs is considered to be the key factor responsible for liver fibrosis [1]. In addition to cytokines and other soluble factors released by Kupffer cells, inflammatory cells and damaged hepatocytes, changes of ECM composition have been suggested to be implicated in the activation of HSCs [6]
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