Tissue Inhibitor of Metalloproteinase 3 Deficiency Disrupts the Hepatocyte E-Cadherin/β-Catenin Complex and Induces Cell Death in Liver Ischemia/Reperfusion Injury

Takehiro Fujii, Sergio Duarte, Eudora Lee, Bibo Ke, Ronald W. Busuttil, Ana J. Coito

Research output: Contribution to journalArticlepeer-review

14 Scopus citations

Abstract

Tissue inhibitor of metalloproteinase (TIMP) 3 is a naturally occurring inhibitor of a broad range of proteases, with key roles in extracellular matrix turnover and in the pathogenesis of various diseases. In this study, we investigated the response of mice lacking TIMP3 (TIMP3−/−) to hepatic ischemia/reperfusion injury (IRI). We report here that TIMP3−/− mice showed an enhanced inflammatory response, exacerbated organ damage, and further impaired liver function after IRI when compared with their wild-type littermates. Loss of TIMP3 led to the cleavage and shedding of E-cadherin during hepatic IRI; the full-length 120-kDa E-cadherin and the ratio of 38-kDa C-terminal fragment/120-kDa E-cadherin were decreased and increased, respectively, in TIMP3−/− livers after IRI. Moreover, GI254023X, a potent inhibitor of a disintegrin and metalloprotease (ADAM) 10, was capable of partially rescuing the expression of E-cadherin in the TIMP3-null hepatocytes. The proteolysis of E-cadherin in the TIMP3−/− livers was also linked to the loss of β-catenin from the hepatocyte membranes and to an increased susceptibility to apoptosis after liver IRI. In a similar fashion, depression of the E-cadherin/β-catenin complex mediated by TIMP3 deletion and knockdown of β-catenin by small interfering RNA were both capable of inducing caspase activation in isolated hepatocytes subjected to H2O2 oxidative stress. Hence, these results support a protective role for TIMP3 expression in sheltering the hepatocyte E-cadherin/β-catenin complex from proteolytic processing and inhibiting apoptosis after hepatic IRI.

Original languageEnglish (US)
Pages (from-to)113-126
Number of pages14
JournalLiver Transplantation
Volume26
Issue number1
DOIs
StatePublished - Jan 1 2020

ASJC Scopus subject areas

  • Surgery
  • Hepatology
  • Transplantation

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