Reactive Oxygen Species Released from Hypoxic Hepatocytes Regulates MMP-2 Expression in Hepatic Stellate Cells

International Journal of Molecular Sciences

Jing Li²  Renhua Fan²  Susu Zhao¹  Leilei Liu²  Shanshan Guo²  Nan Wu²  Wandong Zhang³ 

[1] Department of Pathology, Jiangsu Province Hospital of TCM, Nanjing 210029, China; E-Mail:;Department of Pathology, School of Medicine, Southeast University, Nanjing 210009, China; E-Mails:;Institute for Biological Sciences, National Research Council of Canada, Ottawa, Ontario, K1A 0R6, Canada; E-Mail:

关键词: hypoxia;    hepatocyte;    hepatic stellate cells;    liver fibrosis;    reactive oxygen species;   

DOI  :  10.3390/ijms12042434

来源: mdpi

【 摘 要 】

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.

【 授权许可】

CC BY   
© 2011 by the authors; licensee MDPI, Basel, Switzerland.