TITLE

BALANCE OF TIMP-1 AND MMP-2 DETERMINES N-CADHERIN CLEAVAGE IN HEPATIC STELLATE CELL APOPTOSIS

AUTHOR(S)
Murphy, F.; Waung, J.; Patel, N.; Collins, J.; Brew, K.; Nagase, H.; Arthur, M.J.P.; Benyon, R.C.; Iredale, J.P.
PUB. DATE
April 2003
SOURCE
Gut;Apr2003 Supplement 1, Vol. 52, pA1
SOURCE TYPE
Academic Journal
DOC. TYPE
Article
ABSTRACT
Introduction: The hepatic stellate (HSC) is known to synthesise the majority of excess matrix that characterises liver fibrosis and cirrhosis. Activated HSC also express matrix degrading metalloproteinases (MMPs) and their tissue inhibitors (TIMPs). Whereas during spontaneous recovery from experimental liver fibrosis, there is a fall in the expression of the MMP inhibitor TIMP-1 and an increase in hepatic collagenolytic activity accompanied by HSC apoptosis; in advanced cirrhosis, TIMP-1 expression is maintained, and HSC persist. We have previously demonstrated that TIMP-1 can inhibit apoptosis of HSC by mechanisms involving MMP inhibition. We have studied the role of N-cadherin because it is known to be up regulated during HSC activation and may have a role in determining HSC survival and apoptosis. Aims: To determine the effect of blockade of N-cadherin binding on HSC; observe the fate of N-cadherin during HSC apoptosis; determine which MMP is involved and its direct effect on HSC. Results: By Western blot both rat and human HSC express 135kDa N-cadherin. Blockade of N-cadherin promoted apoptosis of HSC. During apoptosis of HSC there is cleavage of N-cadherin into fragments of 20-100kDa in size, which is protected by TIMP-1 and a selective inhibitor of MMP-2, but not inhibitors of MMP-1 or MMP-3 or a non functional mutant T2G TIMP-1. Active MMP-2 directly cleaves N-cadherin in vitro. Active MMP-2 also promotes apoptosis of HSC. Conclusions: These data suggest that the balance of MMP-2 and TIMP-1 determine HSC survival in hepatic fibrosis via stabilising N-cadherin.
ACCESSION #
9747255

 

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