Disease relevance of Serping1

• Heterozygosity for C1 inhibitor (C1INH) deficiency results in hereditary angioedema [1].
• The gene encoding C1 inhibitor, the major control element of activation of the classical pathway of complement and a major inhibitor of several plasma serine proteases, has been studied only in man, where deficiency of C1 inhibitor results in the dominantly transmitted disease hereditary angioedema [2].
• Previous studies demonstrated that C1 inhibitor (C1INH) protects mice from lipopolysaccharide (LPS)-induced lethal septic shock via a direct interaction with LPS [3].
• The powerful neuroprotective action of C1-inhibitor on brain ischemia-reperfusion injury does not require C1q [4].
• We have studied the effect of C1-INH in C57BL/6 mice with focal transient brain ischemia induced by 30 minutes of occlusion of the middle cerebral artery [4].
• Hence, C1-inh may be a useful agent in the treatment of pneumococcal meningitis [5].
• C1INH may be important in protection from sepsis through enhancement of bacterial uptake by, and/or bactericidal capacity of, phagocytes [6].

High impact information on Serping1

• Increased vascular permeability in C1 inhibitor-deficient mice mediated by the bradykinin type 2 receptor [1].
• However, following injection with Evans blue dye, both homozygous and heterozygous C1INH-deficient mice revealed increased vascular permeability in comparison with wild-type littermates [1].
• This activation pathway is EDTA-resistant (i.e., independent of classical and alternative pathway activation), is regulated by C1 inhibitor, and leads to the generation of hemolytically active membrane attack complexes [7].
• C1 inhibitor prevents Gram-negative bacterial lipopolysaccharide-induced vascular permeability [3].
• A direct role for C1 inhibitor in regulation of leukocyte adhesion [8].

Biological context of Serping1

• The distribution of human C1 inhibitor-expressing cells was qualitatively indistinguishable from that of its mouse counterpart, but expression levels of the transgene were significantly higher [9].
• In vivo biosynthesis of endogenous and of human C1 inhibitor in transgenic mice: tissue distribution and colocalization of their expression [9].
• The C1 inhibitor encoding gene (C1nh) maps to mouse chromosome 2 [10].
• However, the cellular receptor(s) responsible for the catabolism and potential mediation of chemotaxis by C1-INH-protease complexes remained obscure [11].
• The endotoxin-challenged complement-deficient mice failed to clear endotoxin efficiently from the circulation and this led to excess consumption of C1 inhibitor protein (C1 INH), a major regulator of both complement and the contact system of blood coagulation [12].

Anatomical context of Serping1

• In the spleen, production of C1 inhibitor was colocalized with that of a specific marker for white pulp follicular dendritic cells [9].
• Like other serpin-enzyme complexes (SECs), proteinase-complexed C1 inhibitor (C1-INH) is rapidly cleared from the circulation and thought to be a neutrophil chemoattractant, suggesting that complex formation causes structural rearrangements exposing a domain which is recognized by specific cell surface receptors [11].
• Neutral red staining further showed the strong protective effect of C1-INH in cortex, hippocampus, and striatum [13].
• Astrocyte activation induced by ischemia was not affected by C1-INH [13].
• Furthermore, C1-INH markedly inhibited the activation and/or recruitment of microglia/macrophage, as shown by immunohistochemistry [14].

Associations of Serping1 with chemical compounds

• In addition, treatment of the C1INH-deficient mice with an angiotensin-converting enzyme inhibitor (captopril) increased the vascular permeability [1].
• This study demonstrates a stringently regulated expression of both the endogenous and the transgenic human C1 inhibitor gene and reveals local biosynthesis of C1 inhibitor at multiple sites in which the components of the macromolecular C1 complex are also produced [9].
• C1 inhibitor prevents endotoxin shock via a direct interaction with lipopolysaccharide [15].
• Increased susceptibility to endotoxin shock in complement C3- and C4-deficient mice is corrected by C1 inhibitor replacement [12].
• These modifications are fully reversed when C1 is transferred from ES to EA:C1 recovers its ability to react with C2, and C1 INH [16].

Physical interactions of Serping1

• A neoepitope-based enzyme immunoassay for quantification of C1-inhibitor in complex with C1r and C1s [17].

Other interactions of Serping1

• C1 inhibitor and kallikrein [18].
• The asialoglycoprotein receptor was also ruled out to be responsible for the removal of the heavily glycosylated C1-INH.Cs complex, since asialoorosomucoid did not compete for the clearance of C1-INH [11].
• The effect of 15 U C1-INH (intravenously) was evaluated in terms of general and focal neurologic deficits, ischemic volume, neutral red staining (to identify the brain areas subject to ischemic damage), and glial fibrillary acidic protein immunoreactivity (to show astrocytic response) [13].
• Real-time RT-PCR analysis revealed that the post-treatment with Crry-Ig resulted in a significant up-regulation of candidate neuroprotective genes in the injured hemisphere (Bcl-2, C1-Inh, CD55, CD59), as compared to the vehicle control group (P < 0.01, unpaired Student's t test) [19].

Analytical, diagnostic and therapeutic context of Serping1

• Immunohistochemistry in combination with in situ hybridization was applied to localize the sites of C1 inhibitor biosynthesis and to demonstrate its local production in brain, spleen, liver, heart, kidney, and lung [9].
• Molecular cloning, gene structure and expression profile of mouse C1 inhibitor [2].
• The profile of C1 inhibitor expression in mouse liver, lung, heart, kidney, spleen and brain was determined by quantitative northern blot analysis [2].
• Full-length mouse C1 inhibitor cDNA and genomic clones were isolated and characterized as a first step towards the complete characterization of the pattern of C1 inhibitor expression and the production of an animal model of C1 inhibitor deficiency [2].
• The study shows that C1-INH has a strong neuroprotective effect on brain ischemia/reperfusion injury and that its action is independent from C1q-mediated activation of classical pathway [4].

References