Factor VII activating protease (FSAP) inhibits the outcome of ischemic stroke in mouse models

Abstract

Factor VII activating protease (FSAP) is a circulating serine protease, and individuals with the Marburg I (MI) single nucleotide polymorphism (SNP), which results in an inactive enzyme, have an increased risk of stroke. The outcome of ischemic stroke is more marked in FSAP-deficient mice compared to their wild-type (WT) counterparts. Plasma FSAP levels are raised in patients as well as mice after stroke. In vitro, FSAP promotes fibrinolysis by cleavage of fibrinogen, activates protease-activated receptors and decreases the cellular cytotoxicity of histones. Since these are desirable properties in stroke treatment, we tested the effect of recombinant serine protease domain of FSAP (FSAP-SPD) on ischemic stroke in mice. A combination of tissue plasminogen activator (tPA) and FSAP-SPD enhanced clot lysis, improved microvascular perfusion and neurological outcome and reduced infarct volumes in a mouse model of thromboembolic stroke. In the tail bleeding model FSAP-SPD treatment provoked a faster clotting time indicating that it has a pro-coagulant effect that is described before. FSAP-SPD improved stroke outcome and diminished the negative effects of co-treatment with tPA in the transient middle cerebral artery occlusion model. The inactive MI-isoform of FSAP did not have any effects in either model. In mice with FSAP deficiency there were minor differences in the outcomes of stroke but the treatment with FSAP-SPD was equally effective. Thus, FSAP represents a promising novel therapeutic strategy in the treatment of ischemic stroke that requires further evaluation.

Circulating Factor Seven Activating Protease (FSAP) in the Hyperacute Phase of Stroke

“…The changes in FSAP antigen levels are most likely due to activation of pro-FSAP and the formation of inhibitor complexes that are rapidly taken up by cells and removed from the circulation. The short half-life of active FSAP [11] and the time span between the two sample collections (median 53 minutes for LVO patients and median 33 minutes for ICH patients) might be the reason why we do not observe a corresponding increase in FSAP activity and FSAP-AP complex in these groups.…”

“…Combined with the reduction in FSAP antigen that we observe for LVO patients, the ability of FSAP to cleave fibrinogen and therefore promote fibrinolysis [4] indicates a role of FSAP in the pathophysiological mechanisms initiated after ACI/LVO. In addition, mice treated with FSAP-SPD in combination with tPA had improved outcomes caused by better clot lysis and had reduced side effects of tPA treatment after large vessel thromboembolic stroke [11]. Taken together, these findings suggest that FSAP plays a significant role in the pathophysiology of ACI and that further research is needed to explore the precise mechanisms involved and the potential of FSAP-SPD as a future therapeutic agent.…”

“…In plasma collected up to 7 days post stroke, elevated FSAP antigen correlates with outcome in AIS caused by large vessel occlusion (LVO) [9]. Modelling of AIS in FSAP-knockout mice shows increased infarct size [10], and treatment with recombinant serine protease domain (SPD) of FSAP (FSAP-SPD) improved the outcome after large vessel thromboembolic strokes in mice [11].…”

Identification of a Phage Display-Derived Peptide Interacting with the N-Terminal Region of Factor VII Activating Protease (FSAP) Enables Characterization of Zymogen Activation

“…Hence, a lower FSAP activity is linked to an increased disease burden in both mice and humans. We have demonstrated that the recombinant serine protease domain of FSAP has a positive effect on stroke outcomes in mouse models . Pro-FSAP circulates in the blood as a single-chain inactive zymogen, and we hypothesize that pharmacologically activating it could also be of therapeutic interest.…”