Tissue Inhibitor of Metalloproteinase 3 Deficiency Disrupts the Hepatocyte E-Cadherin/β-Catenin Complex and Induces Cell Death in Liver Ischemia/Reperfusion Injury
| Autor: | Fujii, Takehiro, Duarte, Sergio, Lee, Eudora, Ke, Bibo, Busuttil, Ronald W, Coito, Ana J |
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| Rok vydání: | 2020 |
| Předmět: |
Tissue Inhibitor of Metalloproteinase-3
Liver Disease Chronic Liver Disease and Cirrhosis Clinical Sciences Cadherins Oral and gastrointestinal Liver Transplantation Mice Liver Ischemia Reperfusion Injury Hepatocytes Metalloproteases 2.1 Biological and endogenous factors Animals Surgery Aetiology Digestive Diseases beta Catenin |
| Zdroj: | Liver transplantation : official publication of the American Association for the Study of Liver Diseases and the International Liver Transplantation Society, vol 26, iss 1 |
| Popis: | 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 H2 O2 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. |
| Databáze: | OpenAIRE |
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