MMP-9 deficiency shelters endothelial PECAM-1 expression and enhances regeneration of steatotic livers after ischemia and reperfusion injury

Abstract

Background & Aims: Organ shortage has led to the use of steatotic livers in transplantation, despite their elevated susceptibility to ischemia/reperfusion injury (IRI). Matrix metalloproteinase-9 (MMP-9), an inducible gelatinase, is emerging as a central mediator of leukocyte traffic into inflamed tissues. However, its role in steatotic hepatic IRI has yet to be demonstrated. Methods: We examined the function of MMP-9 in mice fed with a high-fat diet (HFD), which developed approximately 50% hepatic steatosis, predominantly macrovesicular, prior to partial hepatic IRI. Results: The inability of MMP-9−/− deficient steatotic mice to express MMP-9 significantly protected these mice from liver IRI. Compared to fatty controls, MMP-9−/− steatotic livers showed significantly reduced leukocyte infiltration, proinflammatory cytokine expression, and liver necrosis. Loss of MMP-9 activity preserved platelet endothelial cell adhesion molecule-1 (PECAM-1) expression, a modulator of vascular integrity at the endothelial cell–cell junctions in steatotic livers after IRI. Using in vitro approaches, we show that targeted inhibition of MMP-9 sheltered the extracellular portion of PECAM-1 from proteolytic processing, and disrupted leukocyte migration across this junctional molecule. Moreover, the evaluation of distinct parameters of regeneration, proliferating cell nuclear antigen (PCNA) and histone H3 phosphorylation (pH3), provided evidence that hepatocyte progression into S phase and mitosis was notably enhanced in MMP-9−/− steatotic livers after IRI. Conclusion: MMP-9 activity disrupts vascular integrity at least partially through a PECAM-1 dependent mechanism and interferes with regeneration of steatotic livers after IRI. Our novel findings establish MMP-9 as an important mediator of steatotic liver IRI.

Neutrophil Extracellular Traps Drive Endothelial-to-Mesenchymal Transition

“…Treatment of ciGEnCs with NETs yielded similar results as obtained for HUVECs ( Figure IIC albumin passage assay was performed, which revealed that the transendothelial passage of albumin was significantly increased in NET-treated HUVECs compared with control HUVECs ( Figure 2E). Because VE-cadherin and CD31 are known substrates of elastase 23 and MMP9, 24 respectively, we assessed whether we could prevent the loss of these junctional proteins and subsequent transendothelial albumin passage by inhibiting the activity of NET-associated elastase and MMP9. Pre-treatment of NETs with sivelestat, a selective inhibitor of elastase, 25 abolished the NET-induced loss of VE-cadherin expression ( Figure 2F and 2G) and reduced transendothelial albumin passage ( Figure 2E).…”

Metalloproteinases in liver fibrosis: current insights

“…Kato et al, 135 Stanton et al, 136 de Meijer et al, 137 Wang et al 138 MCD diet MMP-2, MMP-9, MMP-13…”

Pre-stimulated Mice with Carbon Tetrachloride Accelerate Early Liver Regeneration After Partial Hepatectomy

“…3), we expected the involvement of ECM reconstruction. The reasons why we focused on MMP9 among various candidates involved in the reconstruction of ECM are the following: (1) MMP9 has been reported to be essential for hepatic regeneration [25,26], (2) MMP9 is virtually absent unless the liver is injured [27,28], (3) MMP9 expression can be detected using immunohistochemical analysis in the fetal liver, not adult liver [29,30]. Considering that the inhibition of MMP9 abolishes the effect of pre-stimulation with CCl 4 (Fig.…”