Disease relevance of F7

• In contrast, FVII deficiency is not embryonic lethal, but FVII-/- neonates died from hemorrhage within the first days after birth [1].
• Here, we report a novel treatment strategy with a recombinant adeno-associated virus vector delivering a modified FVII transgene that can be intracellularly processed and secreted as activated FVII (FVIIa) [2].
• The efficacy and safety of an immunoconjugate (icon) molecule, composed of a mutated mouse factor VII (mfVII) targeting domain and the Fc effector domain of an IgG1 Ig (mfVII/Fc icon), was tested with a severe combined immunodeficient (SCID) mouse model of human prostatic cancer and an immunocompetent mouse model of mouse prostatic cancer [3].
• Mice expressing low levels of murine FVII ( approximately 1% of wild-type levels) exhibited a similar pattern of hemosiderin deposition and fibrosis in their hearts [4].
• The immunotherapy tests in SCID mice demonstrated that intratumoral injections of the adenoviral vector encoding the mfVII/human Fc icon resulted in long-term regression of the injected human prostatic tumor and also of a distant uninjected tumor, without associated toxicity to the mice [3].

High impact information on F7

• Blood coagulation in vivo is initiated by factor VII (FVII) binding to its cellular receptor tissue factor (TF) [5].
• FVII-/- mice succumbed perinatally because of fatal haemorrhaging from normal blood vessels [5].
• FVII(-/-)/PC(-/-) embryos, although present at their expected Mendelian frequency, displayed a phenotype that had not been observed in either the FVII or PC singly deficient embryos [6].
• To investigate the role of TF in embryogenesis, we made mutant hTF minigenes whose products either bound FVII/VIIa at a reduced level or lacked the cytoplasmic domain [7].
• Thus, the rescue of TFPIdelta/delta embryos, either by an accompanying homozygous or heterozygous FVII deficiency, suggests that diminishment of FVII activity precludes the need for TFPI-mediated inhibition of the FVIIa/tissue factor coagulation pathway during embryogenesis [8].

Biological context of F7

• Investigation of temporal fluctuations in constant darkness indicated the existence of daily rhythms for TFPI and of true circadian rhythms for FVII [9].
• Characterization of transcriptional regulatory elements in the promoter region of the murine blood coagulation factor VII gene [10].
• All protein domains of hfVII are strictly conserved in mfVII [11].
• The cDNA encoding murine coagulation factor VII (mfVII) was isolated and reconstructed from a lambda Zap cDNA library generated from murine liver mRNA [11].
• Mice completely deficient in FVII were generated via specific deletion of exons 2 to 8, thus deleting the entire coding region of the mature protein [12].

Anatomical context of F7

• The construct conferring highest in vitro FVIII secretion was electroporated into skeletal muscle of FVII null mice in vivo for phenotypic correction using a protocol that minimised tissue injury [13].
• RESULTS: Morphological analysis of the joints 4 days after TF/FVII injection revealed influx of CD4-Mac1+ mononuclear leukocytes into synovial tissue followed by cartilage and bone destruction [14].
• Interaction between macrophages and lymphocytes in sustaining joint inflammation was proved by the requirement of the combined lymphocyte/ monocyte depletion to abolish TF/FVII induced arthritis [14].
• Interestingly, TF/FVII complexes were detected in synovial fluid of 20/40 patients with RA [14].

Associations of F7 with chemical compounds

• Thus, the potential protective effects in vivo of a genetic-based reduction in FVII levels have been investigated in a murine model of acute inflammation, namely lipopolysaccharide (LPS)-induced lethal endotoxaemia [15].
• The expression of the FVII construct was tested in a C2 cell culture system and also when injected directly into mouse muscle [16].
• Murine FVII was activated to FVIIa with human factor Xa and upon reaction with FFR-chloromethyl ketone converted into an active site-blocked TF antagonist, FFR-FVIIa [17].
• Two proteins, FI and FVII, have been purified from a whole worm extract of adult Ascaris suum, using ammonium sulfate precipitation, Sephadex gel filtration and DEAE cellulose chromatography [18].
• BACKGROUND AND OBJECTIVES: Arginine 315 in factor VII (FVII) belongs to a solvent-exposed loop involved in direct interaction with the co-factor (tissue factor, TF), in transmission of TF-induced effects and potentially in FVIIa inactivation [19].

Other interactions of F7

• This resulted in a TF- and FVII-dependent FXa and thrombin generation as measured in the effluent at the outlet of the system [20].

Analytical, diagnostic and therapeutic context of F7

• FVII antigen in media was estimated by immunoassay while FVII activity was assessed by prothrombin-time based and FXa generation assays [19].

References