Cellular effects of factor VII activating protease (FSAP)

Abstract

Factor VII activating protease (FSAP) is a circulating serine protease of broad specificity that is likely to be involved in many pathophysiological processes. The activation of the circulating zymogen form of FSAP by histones, released from damaged cells, underlines its roles in regulating host responses to tissue damage and inflammation. Some of the direct cellular effects of FSAP are mediated through protease-activated receptors (PARs). Knock-down of each one of the four PARs in endothelial cells indicated that PAR-1 and -3 are involved in regulating endothelial permeability in response to FSAP. Overexpression of PARs in cell lines led to the conclusion that PAR-2 and -1 were the main receptors for FSAP. Studies with synthetic peptides and receptor mutants demonstrate that FSAP cleaves PAR-1 and -2 at their canonical cleavage site. However, PAR-1 is not activated by FSAP in all cells, which may be related to other, as yet, undefined factors. Inhibition of apoptosis by FSAP is mediated through PAR-1 and was observed in neurons, astrocytes and A549 cells. FSAP also mediates cellular effects by modulating the activity of growth factors, generation of bradykinin, C5a and C3a generation or histone inactivation. These cellular effects need to be further investigated at the in vivo level.

Proteolytic activation of the epithelial sodium channel (ENaC) by factor VII activating protease (FSAP) and its relevance for sodium retention in nephrotic mice

“…To study whether FSAP may stimulate sodium transport via proteolytic ENaC activation, we performed two-electrode voltage clamp measurements using Xenopus laevis oocytes heterologously expressing human αβγ-ENaC. The recombinant serine protease domain of FSAP (FSAP-SPD-WT; amino acids 292–560) has the same substrate specificity as full-length plasma FSAP [ 11 , 29 , 36 ]. Therefore, we used recombinant FSAP-SPD-WT for our in vitro experiments.…”

“…Both chains are linked by an inter-molecular disulfide bond. Once FSAP is active in the circulation, it can cleave proteins from the hemostasis and complement system as well as cellular regulators such as growth factors and receptors of the protease-activated receptor family (PARs) [ 11 ]. Analysis of substrate preference of FSAP indicates a predilection for clusters of positively charged amino acids [ 24 ].…”

“…Habp2 −/− mice show no marked phenotype in unchallenged conditions but show enhanced liver fibrosis, neointimal formation, infarction after ischemic stroke, and were protected against thrombosis [ 11 ]. In these models, the lack of endogenous FSAP exacerbates the injury response and this is associated with enhanced inflammation.…”

HABP2 Encapsulated by Peripheral Blood-Derived Exosomes Suppresses Astrocyte Autophagy to Exacerbate Neuroinflammatory Injury in Mice with Ischemic Stroke

“…HABP2 is a serine protease that could target PAR1 and permanently activate the signal pathways in the corresponding cells, allowing them to engage in cell proliferation and inflammation . PAR1 has been shown to confer the antiapoptotic effect of HABP2 on neurons, astrocytes, and A549 cells; however, in this study, in vivo experiments validated that HABP2 promoted PAR1 to aggravate IS-related neuroinflammatory injury by enhancing apoptosis. This disparity might be attributed to the different pathological contexts.…”

Hyaladherins May be Implicated in Alcohol-Induced Susceptibility to Bacterial Pneumonia

“…In vivo HABP2 silencing by small interfering RNA attenuated LPS-mediated lung injury and hyperpermeability, indicating a possible therapeutic strategy for bacterial pneumonia in those with AUD-induced barrier dysfunction. Additionally, HABP2 primarily binds to cell surface protease-activated receptors (PAR) ( 125 ), and silencing of PAR1 and PAR3 can attenuate LPS-mediated barrier dysfunction ( 121 ). Mice with PAR2 genetic deletions exhibited severe lung inflammation, neutrophil accumulation, and diminished macrophage and neutrophil bacterial phagocytosis in a model of P. aeruginosa .…”