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TIMP-3 Plays a Key Regulatory Role in the Cleavage of E-Cadherin and Has an Essential Protective Function in Hepatic IRI.

T. Fujii, S. Duarte, R. Busuttil, A. Coito.

Surgery, David Geffen School of Medicine at UCLA, Los Angeles, CA

Meeting: 2017 American Transplant Congress

Abstract number: B122

Keywords: Inflammation, Ischemia, knockout, Liver transplantation, Mice

Session Information

Session Name: Poster Session B: Ischemic Injury and Organ Preservation Session II

Session Type: Poster Session

Date: Sunday, April 30, 2017

Session Time: 6:00pm-7:00pm

 Presentation Time: 6:00pm-7:00pm

Location: Hall D1

Liver ischemia-reperfusion injury (IRI) remains a challenging problem in clinical orthotopic liver transplantation. Tissue inhibitor of metalloproteinases-3 (TIMP-3), an extracellular matrix-associated protein, has been linked to a variety of physiological and pathological functions. In this study, we assessed the functional significance of TIMP-3 expression in well-established in vivo and in vitro models of hepatic IRI. Methods: TIMP-3 deficient mice (TIMP-3-/-) and matched wild-type (TIMP-3+/+) control littermates were submitted to 60-min of partial warm ischemia followed by 6 and 24 h of reperfusion. Isolated TIMP-3+/+ and TIMP-3-/- primary hepatocytes were exposed to 12h of hypoxia followed by 2h of reoxygenation. Hepatocytes isolated from TIMP-3-/- livers were also incubated with ADAM10 inhibitor for 24h after the isolation. Results:Compared to WT controls, TIMP-3-/- mice showed significantly higher AST (6h: 5,090±2,376 vs. 7,882±2,895, 24h: 1,213±420 vs. 2,705±821; each p<.05) levels (IU/L) post-IRI. Loss of TIMP-3 resulted in further lobular architecture disruption and severe necrosis after IRI. TIMP-3-/- livers showed significantly increased Mac-1 and Ly6G leukocyte infiltration (each p<.005) and higher levels of pro-inflammatory cytokines, such as IL-1β, IL-6 and TNF-α (each p<.02) after reperfusion. Moreover, deletion of TIMP-3 gene led to a significant loss of e-cadherin expression in the membranes of hepatocytes near portal areas. The full-length e-cadherin 120 kDa protein was significantly depressed in TIMP-3-/- livers after reperfusion (p<.005), whereas the 35 kDa e-cadherin fragment was notably increased in TIMP-3-/- livers post-reperfusion (p<.02). In vitro, the full-length e-cadherin was markedly depleted in both TIMP-3-/- and TIMP-3+/+ hepatocytes immediately after isolation; however, while e-cadherin expression was significantly restored in TIMP-3+/+ hepatocytes cultured for 12-24h, its expression was not reconstituted in the cultured TIMP-3-/- hepatocytes (p<.05). Conversely, the addition of an ADAM10 inhibitor to the cultured TIMP-3-/- hepatocytes promoted e-cadherin stability in these cells (p<.05). Conclusion: Our results provide strong evidence that TIMP-3 deficiency leads to enhanced inflammation and tissue damage after liver IRI. They also support a key role for TIMP-3 in sheltering the proteolytic cleavage of hepatic e-cadherin, an important mediator of intercellular adhesion and tissue integrity.

CITATION INFORMATION: Fujii T, Duarte S, Busuttil R, Coito A. TIMP-3 Plays a Key Regulatory Role in the Cleavage of E-Cadherin and Has an Essential Protective Function in Hepatic IRI. Am J Transplant. 2017;17 (suppl 3).

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To cite this abstract in AMA style:

Fujii T, Duarte S, Busuttil R, Coito A. TIMP-3 Plays a Key Regulatory Role in the Cleavage of E-Cadherin and Has an Essential Protective Function in Hepatic IRI. [abstract]. Am J Transplant. 2017; 17 (suppl 3). https://atcmeetingabstracts.com/abstract/timp-3-plays-a-key-regulatory-role-in-the-cleavage-of-e-cadherin-and-has-an-essential-protective-function-in-hepatic-iri/. Accessed May 9, 2025.

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