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Matrix Metalloproteinase-2 (MMP-2) Gene Deletion Enhances MMP-9 Activity, Impairs PARP-1 Degradation, and Exacerbates
Hiroyuki Kato1, Sergio Duarte1, Daniel Liu1
1The Dumont-UCLA Transplant Center, Division of Liver and Pancreas Transplantation, Department of Surgery, David Geffen School of Medicine at UCLA, Los Angeles, CA, United States of America.
Abstract:
Hepatic ischemia and reperfusion injury (IRI) is an inflammatory condition and a significant cause of morbidity and mortality after surgery. Matrix metalloproteinases (MMPs) have been widely implicated in the pathogenesis of inflammatory diseases. Among the different MMPs, gelatinases (MMP-2 and MMP-9) are within the most prominent MMPs detected during liver IRI. While the role of MMP-9 in liver damage has been fairly documented, direct evidence of the role for MMP-2 activity in hepatic IRI remains to be established. Due to the lack of suitable inhibitors to target individual MMPs in vivo, gene manipulation is as an essential tool to assess MMP direct contribution to liver injury. Hence, we used MMP-2-/- deficient mice and MMP-2+/+ wild-type littermates to examine the function of MMP-2 activity in hepatic IRI. MMP-2 expression was detected along the sinusoids of wild-type livers before and after surgery and in a small population of leukocytes post-IRI. Compared to MMP-2+/+ mice, MMP-2 null (MMP-2-/-) mice showed exacerbated liver damage at 6, 24, and 48 hours post-reperfusion, which was fatal in some cases. MMP-2 deficiency resulted in upregulation of MMP-9 activity, spontaneous leukocyte infiltration in naïve livers, and amplified MMP-9-dependent transmigration of leukocytes in vitro and after hepatic IRI. Moreover, complete loss of MMP-2 activity impaired the degradation of poly (ADP-ribose) polymerase (PARP-1) in extensively damaged livers post-reperfusion. However, the administration of a PARP-1 inhibitor to MMP-2 null mice restored liver preservation to almost comparable levels of MMP-2+/+ mice post-IRI. Deficient PARP-1 degradation in MMP-2-null sinusoidal endothelial cells correlated with their increased cytotoxicity, evaluated by the measurement of LDH efflux in the medium. In conclusion, our results show for the first time that MMP-2 gene deletion exacerbates liver IRI. Moreover, they offer new insights into the MMP-2 modulation of inflammatory responses, which could be relevant for the design of new pharmacological MMP-targeted agents to treat hepatic IRI.
Insights
Matrix metalloproteinase-2 (MMP-2) deficiency worsens liver injury after ischemia and reperfusion. Loss of MMP-2 impairs poly (ADP-ribose) polymerase-1 degradation, increasing liver damage and inflammation.
Area of Science:
- Hepatology
- Immunology
- Biochemistry
Background:
- Hepatic ischemia and reperfusion injury (IRI) is a major cause of post-surgical complications.
- Matrix metalloproteinases (MMPs), particularly gelatinases MMP-2 and MMP-9, are implicated in inflammatory diseases.
- The specific role of MMP-2 in hepatic IRI pathogenesis requires further elucidation.
Purpose of the Study:
- To investigate the direct contribution of MMP-2 activity to liver injury following IRI.
- To elucidate the mechanisms by which MMP-2 influences inflammatory responses and cell damage in hepatic IRI.
Main Methods:
- Utilized MMP-2 deficient (MMP-2-/-) mice and wild-type (MMP-2+/+) littermates to assess hepatic IRI.
- Analyzed liver damage, leukocyte infiltration, MMP-9 activity, and poly (ADP-ribose) polymerase (PARP-1) degradation.
- Administered a PARP-1 inhibitor to MMP-2 null mice to evaluate its therapeutic potential.
Main Results:
- MMP-2 deficiency exacerbated liver damage, increased mortality, and upregulated MMP-9 activity post-IRI.
- MMP-2 null mice exhibited spontaneous leukocyte infiltration and impaired PARP-1 degradation.
- PARP-1 inhibition in MMP-2 null mice significantly preserved liver function post-IRI.
Conclusions:
- MMP-2 gene deletion worsens hepatic IRI, highlighting its protective role.
- MMP-2 modulates inflammatory cell infiltration and PARP-1 degradation, impacting liver injury severity.
- Targeting MMP-2 or its downstream pathways, like PARP-1, may offer novel therapeutic strategies for hepatic IRI.
