The findings indicate that HABP2, although primarily localized in the plasma, is upregulated in the lung endothelium with LPS-induced ALI and in cultured human pulmonary ECs. The enzymatic activity of HABP2 is differentially regulated by HA, with HMW-HA inhibiting HABP2 protease activity and LMW-HA binding to the PABD of HABP2 and stimulating activity. Activated HABP2 induces protease-activated receptor signaling in ECs, which leads to activation of the actin regulatory molecules RhoA and ROCK and endothelial barrier disruption. The barrier-disruptive role of HABP2 is further confirmed by vascular silencing of HABP2 expression, which attenuated the vascular leakiness observed in LPS- and ventilator-induced lung injury.

Title:
Hyaluronic Acid Binding Protein 2 Is a Novel Regulator of Vascular Integrity

Authors and Source:
Mambetsariev N et al. Arterioscler Thromb Vasc Biol. 2010 Mar;30(3):483-490.

FSAP was found to activate pro-uPA to uPA but, over time, to decrease the activity of uPA in cultured EC and VSMC. Protein levels of uPA were reduced and the enzymatic activity of FSAP was required for this. In contrast, an increase in the gelatinase activity (MMP-2 and -9) was observed, without changes in the levels of individual proteins. FSAP caused this through a non-proteolytic mechanism. However, there was no regulation of the mRNA levels for uPA, tPA, MMP-2 and -9. Also the levels of the gelatinase inhibitors, i.e. the tissue inhibitors of matrix metalloproteinases (TIMPs), were not affected. In a similar manner as in vitro, FSAP reduced uPA activity and increased gelatinase activity in vessel walls in the mouse vascular injury model.

Title:
Factor Seven activating protease (FSAP); A key regulator of pericellular proteolysis.

Authors and Source:
J Daniel, O Uslu, K Hersemeyer, O Rannou, L Muhl, KT Preissner, D Sedding, SM Kanse
Poster presentation ISTH 2009: AS-TH-058

Based upon the observation (i) that FSAP is present in atherosclerotic plaques and (ii) that FSAP inhibits vascular smooth muscle cell activation in vitro, they analysed the effect of wild-type (WT)and mutant (M1) FSAP on neo-intima formation in vivo.

In an animal model (“mouse-femoral artery after wire-induced injury”) they found that wild type-FSAP led to a 70 % reduction in neo-intima formation, while FSAP-M1 had no effect. This difference in neo-intima formation was related to a difference between wild-type FSAP and FSAP-MI in cleavage activity towards platelet-derived growth factor (PDGF).

The authors conclude that FSAP has a protective function in the vasculature, and that the MI polymorphism might be clinically relevant in re-stenosis.

Authors and Source:
Sedding et al., J Exp Med, , 2006 Vol. 203, No. 13, December 25: 2801–2807

Title:
The G534E polymorphism of the gene encoding the factor VII–activating protease is associated with cardiovascular risk due to increased neointima formation

The authors analysed the role of FSAP in chronic liver injury in a murine model. They found that FSAP in the liver was transiently increased in the acute phase reaction but decreased during chronic fibrogenesis. The latter may result in increased PDGF-induced myoblast activity, thus promoting fibrogenesis.

Authors and Source:
Roderfeld et al., Liver Int 2009 May;29(5):686-91

Title:
Altered factor VII activating protease expression in murine hepatic fibrosis and its influence on hepatic stellate cells