Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0042373 (vascular disease)
 17,070 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The isolation and characterization of six human cysteine proteinase inhibitors is reported. Their distribution in human biological fluids is also described and discussed with respect to physiological function. Studies on kininogen and cystatin C with respect to structure-function relationships and, as a result of the cystatin C studies, a general model for the mechanism of cysteine proteinase inhibition by cystatins are presented. The model was used for the construction of synthetic inhibitors which showed good inhibitory properties against papain and the streptococcal cysteine proteinase. Structures of cDNA and gene for normal human cystatin C are accounted for, as well as studies on the cystatin C gene in patients suffering from hereditary cystatin C amyloid angiopathy (HCCAA). As a result of this an RFLP that showed total co-segregation with the disease was found. It was concluded that the disease is caused by a point mutation in the cystatin C structural gene and that the RFLP will be a most useful tool for diagnosis of HCCAA. The production of recombinant cystatin C in E. coli is also reported and its possible use for treatment of HCCAA is discussed.
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PMID:Human cysteine proteinase inhibitors. Isolation, physiological importance, inhibitory mechanism, gene structure and relation to hereditary cerebral hemorrhage. 307 20

We evaluated the pulmonary circulatory effects of emphysema produced by papain in 6 dogs that received 4 weekly treatments of papain administered by aerosolization. A control group of 6 dogs received saline treatments. Hemodynamic measurements were performed during normoxic and hypoxic (10% oxygen) ventilation approximately 3 and 6 months after treatment. Baseline hemodynamic parameters were comparable in both groups and were unchanged at 6 months in the control group. In the papain-treated group at 6 months, there were significant reductions in PaO2 (95 +/- 4 to 79 +/- 3 mm Hg, p less than 0.005) and increases in mean pulmonary artery pressure (12 +/- 1 to 18 +/- 3 mm Hg, p less than 0.05) and pulmonary vascular resistance (2.0 +/- 0.3 to 6.2 +/- 2.1 units, p less than 0.01). Morphometric evaluation demonstrated increased medial thickness in muscular pulmonary arteries less than 50 mu in size. Morphologic evaluation confirmed the presence of panlobular emphysema with papain administration. We conclude that chronic emphysema produced in dogs by aerosol administration of papain results in elevated pulmonary artery pressure, which is characterized pathologically by medial hypertrophy of small pulmonary arteries. This model appears suitable for further study of the pathogenesis of pulmonary vascular disease associated with chronic lung disease.
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PMID:Pulmonary vascular structural and functional changes in papain-induced emphysema in dogs. 363 41

Recombinant mouse (Mus musculus) and rat (Rattus norvegicus) cystatin C were produced by expression in Escherichia coli, isolated and functionally characterized. The mouse and rat inhibitors were both fully active in titrations of papain. Determination of equilibrium constants for dissociation (Ki) for their complexes with the target proteinase, cathepsin B, produced values not largely different from that for human cystatin C (Ki 0.07-0.13 nM). Rabbit antisera against mouse and rat cystatin C were produced and used for improved affinity purification of the recombinant inhibitors. Affinity purified immunoglobulins isolated from the antiserum against mouse cystatin C were used for construction of a sensitive enzyme-linked immunosorbent assay. The assay was used to demonstrate a high degree of immunological cross-reactivity between mouse and rat cystatin C and could be used for cystatin C quantification in mouse and rat tissue homogenates. All tissues analyzed contained cystatin C, with a relative content very similar to that of human tissues. For all species, brain tissue contained the highest cystatin C amounts and liver the lowest, whereas kidney, spleen and muscle tissues were intermediate in content. In the mouse, a notable high cystatin C content in parotid gland tissue was observed. The high degree of similarity in distribution pattern and functional properties for mouse, rat and human cystatin C indicates that a murine model should be relevant for studies of the human disease, hereditary cystatin C amyloid angiopathy.
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PMID:Mouse and rat cystatin C: Escherichia coli production, characterization and tissue distribution. 876 Nov 77

Hereditary cystatin C amyloid angiopathy (HCCAA) is an autosomal dominant condition in which the patients suffer at an early age from repeated cerebral haemorrhages. The development of HCCAA is directly linked to a Leu-68-->Gln (L68Q) mutation in the cystatin C protein sequence. The concentration of cystatin C in cerebrospinal fluid (CSF) of HCCAA patients is markedly diminished and cultivated monocytes from affected individuals accumulate cystatin C. The goal of this work was to characterize cystatin C isolated from CSF and monocyte cultures originating from healthy persons and HCCAA patients with respect to the L68Q mutation. Cystatin C was isolated by carboxymethylpapain affinity chromatography. Proteins from CSF and monocyte cultures that bound specifically to the carboxymethylated papain column were resolved by reverse-phase HPLC chromatography and tryptic peptides were subsequently analysed by matrix-assisted laser desorption ionization MS. No evidence for mutated cystatin C protein was found in CSF samples from healthy subjects or HCCAA patients, but approx. 60% of the protein was found to be hydroxylated on Pro-3. No evidence was found for secretion of mutated cystatin C from HCCAA monocytes. However, we obtained evidence for the presence of mutated cystatin C in HCCAA monocytes. These results support the conclusion that the mutated cystatin C is retained in association with the monocytes and not secreted. An increased intracellular concentration would presumably promote the aggregation and denaturation of the mutated cystatin C, leading to the formation of amyloid fibrils and cell death.
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PMID:Hereditary cystatin C amyloid angiopathy: monitoring the presence of the Leu-68-->Gln cystatin C variant in cerebrospinal fluids and monocyte cultures by MS. 944 75

Human cystatin C (HCC) is a family 2 cystatin inhibitor of papain-like (C1) and legumain-related (C13) cysteine proteases. In pathophysiological processes, the nature of which is not understood, HCC is codeposited in the amyloid plaques of Alzheimer's disease or Down's syndrome. The amyloidogenic properties of HCC are greatly increased in a naturally occurring L68Q variant, resulting in fatal cerebral amyloid angiopathy in early adult life. In all crystal structures of cystatin C studied to date, the protein has been found to form 3D domain-swapped dimers, created through a conformational change of a beta-hairpin loop, L1, from the papain-binding epitope. We have created monomer-stabilized human cystatin C, with an engineered disulfide bond (L47C)-(G69C) between the structural elements that become separated upon domain swapping. The mutant has drastically reduced dimerization and fibril formation properties, but its inhibition of papain is unaltered. The structure confirms the success of the protein engineering experiment to abolish 3D domain swapping and, in consequence, amyloid fibril formation. It illustrates for the first time the fold of monomeric cystatin C and allows verification of earlier predictions based on the domain-swapped forms and on the structure of chicken cystatin. Importantly, the structure defines the so-far unknown conformation of loop L1, which is essential for the inhibition of papain-like cysteine proteases.
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PMID:Crystal structure of human cystatin C stabilized against amyloid formation. 2017 78

Human cystatin C (hCC) is a small protein belonging to the cystatin family of papain-like cysteine proteinase inhibitors. We review the recent literature concerning structural aspects of hCC related to disease. We focus on the mechanisms of hCC dimerization, oligomerization, and amyloid formation. Amyloid formation is associated with a number of neurodegenerative diseases that affect the independence and quality of life of aging populations. hCC is one of the second-wave proteins that have been found to undergo amyloidosis associated with disease. For hCC, this includes cerebral amyloid angiopathy, as well as a disorder resulting in reduced male fertility.
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PMID:Human cystatin C monomer, dimer, oligomer, and amyloid structures are related to health and disease. 2776 18

Human cystatin C (hCC), a member of the superfamily of papain-like cysteine protease inhibitors, is the most widespread cystatin in human body fluids. This small protein, in addition to its physiological function, is involved in various diseases, including cerebral amyloid angiopathy, cerebral hemorrhage, stroke, and dementia. Physiologically active hCC is a monomer. However, all structural studies based on crystallization led to the dimeric structure formed as a result of a three-dimensional exchange of the protein domains (3D domain swapping). The monomeric structure was obtained only for hCC variant V57N and for the protein stabilized by an additional disulfide bridge. With this study, we extend the number of models of monomeric hCC by an additional hCC variant with a single amino acid substitution in the flexible loop L1. The V57G variant was chosen for the X-ray and NMR structural analysis due to its exceptional conformational stability in solution. In this work, we show for the first time the structural and dynamics studies of human cystatin C variant in solution. We were also able to compare these data with the crystal structure of the hCC V57G and with other cystatins. The overall cystatin fold is retained in the solute form. Additionally, structural information concerning the N terminus was obtained during our studies and presented for the first time. DATABASE: Crystallographic structure: structural data are available in PDB databases under the accession number 6ROA. NMR structure: structural data are available in PDB and BMRB databases under the accession numbers 6RPV and 34399, respectively.
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PMID:NMR and crystallographic structural studies of the extremely stable monomeric variant of human cystatin C with single amino acid substitution. 3133 77