Reactive Oxygen Species Released from Hypoxic Hepatocytes Regulates MMP-2 Expression in Hepatic Stellate Cells |
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Authors: | Li Jing Fan Renhua Zhao Susu Liu Leilei Guo Shanshan Wu Nan Zhang Wandong Chen Pingsheng |
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Affiliation: | Department of Pathology, School of Medicine, Southeast University, Nanjing 210009, China; E-Mails: 8218lijing@sina.com (J.L.); 493069029@qq.com (R.F.); lilyy778@163.com (L.L.); 973573379@qq.com (N.W.); 153777836@qq.com (S.G.). |
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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. |
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Keywords: | hypoxia hepatocyte hepatic stellate cells liver fibrosis reactive oxygen species |
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