Anti-angiogenic action of plasma hyaluronan binding protein in human umbilical vein endothelial cells

Abstract

Abstract.The kringle domain is a triple loop structure present in angiostatin and endostatin. The disulfide bond-linked kringle architectures have been known to be essential for anti-angiogenic activity. Plasma hyaluronan binding protein (PHBP) is a novel serine protease which consists of three epidermal growth factor (EGF) domains, a kringle domain, and a serine protease domain. PHBP can be cleaved autocatalytically to generate activity and is highly expressed in the human blood and liver. To determine the anti-angiogenic activities of PHBP, we purified recombinant mouse PHBP from stable cell line overexpressing PHBP and used protein in vivo and in vitro angiogenesis assays. We found that recombinant PHBP inhibits not only angiogenesis in vivo in chorioallantoic membrane (CAM) assay but also the basic fibroblast growth factor (bFGF)-induced proliferation, invasion and tube formation of human umbilical vein endothelial cells (HUVECs) in a dose-dependant manner. Moreover, we found that the kringle domain of PHBP was essential for the antiangiogenic action of PHBP by the deletion mutants. These findings unravel a new function of PHBP as an inhibitor of the proangiogenic phenotype of vascular endothelial cells and demonstrate that the kringle domain of PHBP might be a potent novel inhibitor of activated endothelial cells in vitro and in vivo.

Largazole: From discovery to broad-spectrum therapy

“…12 In fact, this phenomenon is not unique to largazole but rather a characteristic feature of HDAC inhibitors. 48,49 Higher concentrations (>30 nM) additionally induced apoptosis, measured by activation of caspases 3/7. On the transcript and protein levels, the same concentration of largazole strongly upregulated pro-apoptotic members of the BCL2 family of proteins intimately tied to this event.…”

Endometrial gene expression analysis at the time of embryo implantation in women with unexplained infertility

“…VEGF, PIGF, FGF, TGFβ) (Torry, et al, 2007) as well as other factors, can contribute to vascular development and maintenance at the maternal-foetal interface. Hyaluronan-binding protein 2 (HABP2), also known as factor VII-activating protease (FSAP), is an extracellular serine protease, which has been shown to inhibit angiogenesis (Jeon, et al, 2006). HABP2 has also been shown to promote the coagulation cascade by acting as an activator of factor VII, independently of tissue factor, and in the fibrinolytic pathway activating pro-urokinase (Roemisch, et al, 2002;Romisch, et al, 1999) (Figure 4).…”

Factor VII activating protease (FSAP) regulates the expression of inflammatory genes in vascular smooth muscle and endothelial cells

“…In VSMC, FSAP inhibits PDGF-BB-mediated mitogen activated protein kinase (MAPK) activation, cell proliferation and migration through proteolytic cleavage 54,66 . Similarly, inhibition of VEGF by FSAP has also been proposed 83 . On the other hand conversion of the zymogen pro-BMP-2 to active BMP-2 increased its activity towards osteoblastic transformation of cells 84 .…”