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Reactive Oxygen Species Released from Hypoxic Hepatocytes Regulates MMP-2 Expression in Hepatic Stellate Cells
Department of Pathology, School of Medicine, Southeast University, Nanjing 210009, China
Department of Pathology, Jiangsu Province Hospital of TCM, Nanjing 210029, China
Institute for Biological Sciences, National Research Council of Canada, Ottawa, Ontario, K1A 0R6, Canada
* Author to whom correspondence should be addressed.
Received: 7 March 2011; in revised form: 31 March 2011 / Accepted: 2 April 2011 / Published: 7 April 2011
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.
Keywords: hypoxia; hepatocyte; hepatic stellate cells; liver fibrosis; reactive oxygen species
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MDPI and ACS Style
Li, J.; Fan, R.; Zhao, S.; Liu, L.; Guo, S.; Wu, N.; Zhang, W.; Chen, P. Reactive Oxygen Species Released from Hypoxic Hepatocytes Regulates MMP-2 Expression in Hepatic Stellate Cells. Int. J. Mol. Sci. 2011, 12, 2434-2447.
Li J, Fan R, Zhao S, Liu L, Guo S, Wu N, Zhang W, Chen P. Reactive Oxygen Species Released from Hypoxic Hepatocytes Regulates MMP-2 Expression in Hepatic Stellate Cells. International Journal of Molecular Sciences. 2011; 12(4):2434-2447.
Li, Jing; Fan, Renhua; Zhao, Susu; Liu, Leilei; Guo, Shanshan; Wu, Nan; Zhang, Wandong; Chen, Pingsheng. 2011. "Reactive Oxygen Species Released from Hypoxic Hepatocytes Regulates MMP-2 Expression in Hepatic Stellate Cells." Int. J. Mol. Sci. 12, no. 4: 2434-2447.