title: Reactive oxygen species released from hypoxic hepatocytes regulates MMP-2 expression in hepatic stellate cells.
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.
authors: 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.).
authors: Jing
authors: J
authors: Li
authors: Renhua
authors: R
authors: Fan
authors: Susu
authors: S
authors: Zhao
authors: Leilei
authors: L
authors: Liu
authors: Shanshan
authors: S
authors: Guo
authors: Nan
authors: N
authors: Wu
authors: Wandong
authors: W
authors: Zhang
authors: Pingsheng
authors: P
authors: Chen
mesh_terms: D000818:Animals; D015687:Cell Hypoxia; D002460:Cell Line; D005978:Glutathione / Q000378:metabolism; D055166:Hepatic Stellate Cells / Q000166:cytology / Q000378:metabolism; D020778:Matrix Metalloproteinase 2 / Q000235:genetics / Q000378:metabolism*; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017382:Reactive Oxygen Species / Q000378:metabolism*; D015398:Signal Transduction; D015854:Up-Regulation
chemical_list: D016328:NF-kappa B; D012333:RNA, Messenger; D017382:Reactive Oxygen Species; D020778:Matrix Metalloproteinase 2; D005978:Glutathione