Altered fibrinogen γ-chain cross-linking in mutant fibrinogen-γ^Δ5 mice drives acute liver injury.

ABSTRACT:

Background

Hepatic deposition of cross-linked fibrin(ogen) occurs alongside platelet accumulation as a hallmark of acetaminophen (APAP)-induced liver injury.

Objectives

We sought to define the precise role of the fibrinogen γ-chain C-terminal integrin α_IIbβ₃ binding domain in APAP-induced liver injury.

Methods

Mice expressing mutant fibrinogen incapable of engaging integrin α_IIbβ₃ due to a C-terminal fibrinogen γ-chain truncation (mutant fibrinogen-γ^Δ5 [Fibγ^Δ5] mice) and wild-type mice were challenged with APAP (300 mg/kg, intraperitoneally).

Results

We observed an altered pattern of fibrin(ogen) deposition in the livers of APAP-challenged Fibγ^Δ5 mice. This led to the unexpected discovery that fibrinogen γ-chain cross-linking was altered in the livers of APAP-challenged Fibγ^Δ5 mice compared with that in wild-type mice, including absence of γ-γ dimer and accumulation of larger molecular weight cross-linked γ-chain complexes. This finding was not unique to the injured liver because activation of coagulation did not produce γ-γ dimer in plasma from Fibγ^Δ5 mice or purified Fibγ^Δ5 fibrinogen. Sanger sequencing predicted that the fibrinogen-γ^Δ5 γ-polypeptide would terminate at lysine residue 406, but liquid chromatography tandem mass spectrometry analysis revealed that this critical lysine residue was absent in purified fibrinogen-γ^Δ5 protein. Interestingly, hepatic deposition of this uniquely aberrantly cross-linked fibrin(ogen) in Fibγ^Δ5 mice was associated with exacerbated hepatic injury, an effect not recapitulated by pharmacologic inhibition of integrin α_IIbβ₃.

Conclusion

The results indicate that fibrinogen-γ^Δ5 lacks critical residues essential to form γ-γ dimer in response to thrombin and suggest that hepatic accumulation of abnormally cross-linked fibrin(ogen) can exacerbate hepatic injury.

SUBMITTER: Poole LG 

PROVIDER: S-EPMC10524487 | biostudies-literature | 2023 Aug

REPOSITORIES: biostudies-literature