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PubMed2006

Cystatin C, left ventricular hypertrophy, and diastolic dysfunction: data from the Heart and Soul Study.

BACKGROUND: Impaired kidney function, as measured by serum cystatin C, is associated with risk of incident heart failure. Whether cystatin C is associated with preclinical cardiac structural abnormalities is unknown. We evaluate whether cystatin C is associated with left ventricular hypertrophy, diastolic dysfunction, and systolic dysfunction among 818 outpatients with coronary artery disease who were free of clinical heart failure. METHODS AND RESULTS: The 818 study participants were categorized into quartiles based on serum cystatin C concentrations, with < or =0.91 mg/L constituting the lowest quartile (I) and > or =1.28 mg/L constituting the highest (IV). Left ventricular hypertrophy (left ventricular mass index >90 g/m(2) by truncated ellipsoid method), diastolic dysfunction (impaired relaxation, pseudo-normal, or restrictive filling patterns) and systolic dysfunction (left ventricular ejection fraction < or =50%) were determined by echocardiography. Left ventricular hypertrophy was present in 68% of participants in quartile IV, compared with 44% of those in quartile I (adjusted odds ratio [OR] 2.17; 95% confidence interval [CI] 1.34 to 3.52; P = .002). Diastolic dysfunction was present in 52% of participants in quartile IV, compared with 24% of those in quartile I (adjusted OR 1.79; 95% CI 1.04 to 3.11; P = .04). Systolic dysfunction was present in 12% of those in quartile IV, compared with 6% of those in quartile I (adjusted OR 1.83; 95% CI 0.75 to 4.46; P = .15). CONCLUSION: Higher cystatin C concentrations are strongly associated with left ventricular hypertrophy and diastolic dysfunction in outpatients with coronary artery disease and without heart failure.

Aged↗
PubMed2000

Cystatin C, an early indicator for incipient renal disease in rheumatoid arthritis.

Rheumatoid arthritis (RA) is a chronic disease requiring potential nephrotoxic therapy with nonsteroidal antiinflammatory drugs (NSAIDs) and disease modifying antirheumatic drugs (DMARDs). The rationale of our study was to examine the renal status of patients suffering from prolonged RA by means of plasma cystatin C, a new parameter of renal function. Fifty-six patients affected with RA for more than 5 years, and treated with NSAIDs for more than 50 months, were included in the study. Besides conventional markers of renal function (i.e. plasma creatinine, estimated glomerular filtration rate, creatinine clearance), we analysed plasma cystatin C by an automated, nephelometric immunoassay on a Behring nephelometer. Sixty percent of the RA patients exhibited elevated levels of plasma cystatin C, whereas only three out of 56 patients showed an elevated plasma creatinine, even though the creatinine clearance was decreased in 57% of these patients. Cystatin C exhibited a by far better correlation with creatinine clearance than plasma creatinine. In conclusion, patients with prolonged RA for more than 50 months, show a disturbed renal function despite normal plasma creatinine. Elevated cystatin C indicates such incipient renal disease, and is, not least because of a simple, well reproducible technique, more recommendable for screening purposes than tedious clearance determinations.

Aged↗
PubMed1987

Human cystatins in normal and diseased tissues--a review.

Immunohistochemica and quantitative immunochemical methods were used to demonstrate the presence of two cysteine proteinase inhibitors, cystatins A and B, in normal and diseased tissues. Cystatin A is expressed in squamous epithelia, neutrophil granulocytes, and dendritic reticulum cells of the lymphatic tissues. Its concentration is increased in inflammatory skin diseases and decreases after the malignization of squamous epithelia. Cystatin B is seen in wet squamous epithelia, and in the cells of monocyte-macrophage series, where its concentration varies depending on the activation state of the cells. In the malignant keratinocytes cystatin B follows the behaviour of cystatin A.

Cystatin B↗
PubMed1988

Mutation in cystatin C gene causes hereditary brain haemorrhage.

Hereditary cystatin C amyloid angiopathy (HCCAA) is an autosomal dominant disorder in which a cysteine proteinase inhibitor, cystatin C, is deposited as amyloid fibrils in the cerebral arteries of patients and leads to massive brain haemorrhage and death in young adults. A full length cystatin C cDNA probe revealed a mutation in the codon for leucine at position 68 which abolishes an Alu I restriction site in the cystatin C gene of HCCAA patients. The Alu I marker has been used to show that this mutation is transmitted only in affected members of all eight families investigated, and that the mutated cystatin C gene causes HCCAA.

Cerebral Hemorrhage↗
PubMed2000

Analysis of expressed sequence tags of retinal pigment epithelium: cystatin C is an abundant transcript.

In order to identify genes that are expressed in the retinal pigment epithelium (RPE), randomly chosen clones of a cDNA library of cultured human foetal RPE cells were analyzed by sequencing. Of 164 informative expressed sequence tags (ESTs), 88 matched the sequences of 74 genes for proteins of known or presumed function. Approximately a third of these represented genes with involvement in gene/protein expression, with a major subcategory concerned with protein turnover. In particular, the gene coding for precursor cystatin C was represented by 3 independent ESTs, and plaque hybridization estimated the frequency of cystatin C clones in the library to be 1.3%. Cystatin C mRNA in cultured RPE cells was confirmed by Northern blotting and by reverse transcription polymerase chain reaction (RT-PCR) with identification of the cystatin C sequence as the product of the reaction. The survey also revealed 25 novel human sequences representing genes that are active in RPE. One of these was localized near a recently identified, new autosomal recessive retinitis pigmentosa locus. In conclusion, the findings specifically demonstrate the unexpected presence of cystatin C mRNA at fairly high abundance in cultured human RPE cells, and, more generally, serve as a model study establishing the usefulness of the EST approach for further characterizing the molecular basis of the activities of the RPE.

Cells, Cultured↗
PubMed2004

Association of human neuroglobin with cystatin C, a cysteine proteinase inhibitor.

Neuroglobin (Ngb) is a newly discovered globin that is expressed in vertebrate brain. It has been reported that Ngb levels increase in neurons in response to oxygen deprivation, and that Ngb protects neurons from hypoxia. However, the mechanism of this neuroprotection remains unclear. In the present study, we identified human cystatin C, a cysteine proteinase inhibitor, as an Ngb-binding protein by using a yeast two-hybrid system. Surface plasmon resonance experiments verified that Ngb binds to cystatin C dimers, not to the monomers. Because both intracellular cystatin C and the amyloidogenic variant of cystatin C form dimers, Ngb may modulate the intracellular transport (or secretion) of cystatin C to protect against neuronal death under conditions of oxidative stress and/or it may have a role in the development of neurodegenerative diseases.

Amino Acid Sequence↗
PubMed1996

The importance of the second hairpin loop of cystatin C for proteinase binding. Characterization of the interaction of Trp-106 variants of the inhibitor with cysteine proteinases.

The single Trp of human cystatin C, Trp-106, is located in the second hairpin loop of the proteinase binding surface. Substitution of this residue by Gly markedly altered the spectroscopic changes accompanying papain binding and reduced the affinity for papain, actinidin, and cathepsins B and H by 300-900-fold. The decrease in affinity indicated that the side chain of Trp-106 contributes a similar free energy, -14 to -17 kJ.mol-1, to the binding to all four cysteine proteinases, corresponding to about 20-30% of the total binding energy. Replacement of Trp-106 by Phe led to a smaller (30-120-fold) decrease in affinity for the four enzymes than Gly substitution. The binding energy of the Phe residue corresponded to 20-45% of that of Trp, showing that a phenyl group can only partly substitute for the indole ring. The reduced affinities of the cystatin C Trp-106 variants for all proteinases studied were due almost exclusively to increased dissociation rate constants. The second hairpin loop thus contributes to the binding primarily by keeping cystatin C anchored to the proteinase once the complex has been formed. This role is partly in contrast to that of the N-terminal region, which increases the affinity of cystatin C for cathepsin B by increasing the association rate constant. Removal of the N-terminal region of the Trp-106-->Gly variant by proteolytic cleavage substantially weakened the binding to papain and cathepsin B. The resulting affinity indicated that the first hairpin loop (the "QVVAG-region"), which is the only region of the proteinase binding surface remaining intact in the truncated variant, contributes 40-60% of the total free energy of binding of cystatin C to both proteinases.

Base Sequence↗
PubMed1999

Importance of the second binding loop and the C-terminal end of cystatin B (stefin B) for inhibition of cysteine proteinases.

The importance of residues in the second hairpin loop and the C-terminal end of mammalian cystatin B for binding of proteinases was elucidated by mutagenesis of the bovine inhibitor. Bovine cystatin B was modeled onto the crystal structure of the human inhibitor in complex with papain with minimal structural changes. Substitution of the two deduced contact residues in the second hairpin loop, Leu-73 and His-75, with Gly resulted in appreciably reduced affinities for papain and cathepsins H and B. These losses indicated that the two residues together contribute 20-30% of the free energy of binding of cystatin B to these enzymes and that Leu-73 is responsible for most of this contribution. In contrast, the small decrease in the affinity for cathepsin L suggested that the second hairpin loop is less important for inhibition of this proteinase. Replacement of the contact residue in the C-terminal end, Tyr-97, with Ala resulted in losses in affinity for papain and cathepsins L and H that were consistent with Tyr-97 contributing 6-12% of the energy of binding of cystatin B to these enzymes. However, this substitution minimally affected the affinity for cathepsin B, indicating that the C-terminal end is of limited importance for binding of this proteinase. All affinity decreases were due predominantly to increased dissociation rate constants. These results show that both the second hairpin loop and the C-terminal end of cystatin B contribute to anchoring the inhibitor to target proteinases, each of the two regions interacting with a different domain of the enzyme. However, the relative contributions of these two interactions vary with the proteinase.

Amino Acid Sequence↗
PubMed2004

Effect of polysaccharides and human plasma lipoproteins on the secretion of cystatin C by peritoneal macrophages from normal and tumor bearing mice.

Intact peritoneal macrophages in vitro secreted the cysteine proteinase inhibitor cystatin C. Polysaccharides stimulated cystatin C secretion: lipopolysaccharide < carboxymethylated beta-D-glucan < sulfoethylated beta-D-glucan. Human plasma low-density- (LDL) and high-density lipoproteins (HDL) are still more potent inducers of cystatin C secretion by macrophages. Peritoneal macrophages from mice with experimental HA-1 hepatoma compared to those from intact mice secreted more cystatin C with maximum polysaccharide-stimulated secretion after 30 min of incubation. LDL and HDL induced cystatin C secretion by tumor macrophages also.

Animals↗
PubMed2002

The relationship between serum creatinine, serum cystatin C and glomerular filtration rate in pediatric renal transplant recipients: a pilot study.

Serum cystatin C more accurately reflects glomerular filtration rate (GFR) in pediatric renal transplant recipients than serum creatinine. Nineteen pediatric renal transplant recipients, 15 male and 4 female, ranging in age from 8.35 yr to 19.06 yr (median 13.52 yr), were enrolled in the study over an 18-month period. Twenty-eight measurements of 99mTc-DTPA GFR were compared with simultaneous measurements of serum cystatin C and Cr. Linear regression analysis, Pearson correlation coefficients and analysis of variance (anova) were used to determine the relationship between creatinine, cystatin C and GFR. The correlation coefficients (R2) for the relationship of 1/Cr to DTPA-GFR and for 1/cystatin C to DTPA-GFR were 0.63 and 0.58, respectively. There was no significant difference between serum cystatin C and serum creatinine as markers of GFR. Serum cystatin C, which costs more to measure than serum creatinine, offers no advantage in monitoring the renal function of pediatric renal transplant recipients.

Adolescent↗
PubMed2000

Serum and cerebrospinal fluid cystatin C levels in vascular and Alzheimer's dementia.

INTRODUCTION: Cystatin C, a cysteine protease inhibitor, has been implicated in the neurodegenerative and repair processes of the nervous system, and the deposition of the same protein together with beta amyloid peptide was found as cerebral amyloid angiopathy (CAA) in different types of dementias. OBJECTIVE AND METHODS: Because of the differential diagnostic importance, serum and cerebrospinal fluid (CSF) cystatin C levels of 24 late onset Alzheimer's demented (AD) and 16 ischemic type of vascular demented (VD) probands were compared with 17 aged control (AC) persons. RESULTS: The serum and CSF cystatin levels were found in the normal range in all groups. The ischemic VD probands had the tendency to have higher cystatin C levels than the AD. No correlation has been found with the severity and duration of dementia and with the other measured parameters. CONCLUSION: These results indicate that lower than normal CSF cystatin C level is not a diagnostic marker in ischemic VD and CAA related to AD.

Aged↗
PubMed2001

Expression of cysteine proteinases cathepsins B and K and of cysteine proteinase inhibitor cystatin C in giant cell tumor of tendon sheath.

The expression of cysteine proteinases cathepsins B and K and of the endogenous inhibitor of cysteine proteinases, cystatin C, was investigated in tissue specimens of patients with giant cell tumor of tendon sheath (GCTTS). Expression of both enzymes was examined by immunohistochemistry in tissue specimens of 14 patients with GCTTS. Applying double-labeling techniques, the coexpression of cathepsin B and its major endogenous inhibitor cystatin C was additionally studied. Cells expressing the respective proteins were further characterized with the macrophage markers HAM56 and anti-CD68 (clone PG-M1). Cathepsin B could be detected in numerous HAM56-positive mononuclear cells (MC), but only in very few giant cells (GC). In contrast, cathepsin K was predominantly identified in GC that were also strongly immunoreactive for cystatin C and CD68. Coexpression of cathepsin B and cystatin C occurred only in a few MC. The strong expression of both cathepsin B and K suggests that in GCTTS, bone erosion might be mediated not only by pressure of the proliferative tissue, but also by matrix-degrading cysteine proteinases. Because previous studies showed that osteoclasts express high levels of CD68, cathepsin K, and cystatin C but not of cathepsin B, our study contributes to the view that GC of GCTTS and osteoclasts are closely associated.

Adult↗
PubMed2002

Serum cystatin C as a marker of the renal function in patients with spinal cord injury.

OBJECTIVE: To investigate the relationship between serum cystatin C, serum creatinine, and (51)Cr-EDTA-clearance in patients with spinal cord injury. SETTING: The Spinal Cord Unit, Viborg-Kjellerup County Hospital. METHODS: Twenty-four men and seven women aged 20.3 to 68.0 years with motor complete spinal cord injury (ASIA A or B) were included. Serum cystatin C was measured by an automated particle-enhanced nephelometric immunoassay (Dade Behring), serum creatinine by an enzymatic method (Vitros 950), and (51)Cr-EDTA-clearance by a multiple plasma sample method. RESULTS: A linear relationship was found between (51)Cr-EDTA-clearance and the reciprocal values of cystatin C and creatinine. The correlation coefficient between (51)Cr-EDTA-clearance and 1/cystatin C was 0.72 compared to the correlation coefficient between (51)Cr-EDTA-clearance and 1/creatinine being 0.26. Comparison of the area under the curves in the non-parametric receiver operating characteristics (ROC) plots for serum cystatin C (area under the curve (AUC)=0.912; SE=0.065), and serum creatinine (AUC=0.507; SE=0.115) revealed significant differences (P-values=0.0005). CONCLUSION: In patients with spinal cord injury serum cystatin C is a better marker of the renal function compared to serum creatinine.

Adult↗
PubMed2001

Cystatin C deficiency is associated with the progression of small abdominal aortic aneurysms.

BACKGROUND: The cysteine protease inhibitor cystatin C may play a role in the development and progression of abdominal aortic aneurysms (AAAs). METHODS: From a mass screening trial of men aged 65-73 years, 151 small AAAs were followed for a mean of 2.9 years. Of these patients, 142 had serum samples taken to determine the levels of cystatin C, creatinine and C-reactive protein (CRP). RESULTS: Serum cystatin C concentration correlated negatively with AAA size (r = - 0.22 (95 per cent confidence interval (c.i.) - 0.59 to - 0.02)) and annual expansion rate (r = - 0.24 (95 per cent c.i. - 0.75 to - 0.05)), persisting after adjustment for renal function, smoking, diastolic blood pressure, CRP, age and AAA size. Creatinine clearance and CRP did not correlate with size or expansion rate. Thirty-one AAAs had expanded to over 50 mm, when operation was recommended. The serum level of cystatin C was a significant predictor of this occurrence, with a sensitivity and specificity of 61 and 57 per cent respectively. However, initial AAA size had the optimal sensitivity and specificity (both 81 per cent) in this regard. CONCLUSION: Deficiency of cystatin C was associated with increased aneurysm size and expansion rate, possibly due to lack of inhibition of cysteine proteases.

Aged↗
PubMed1997

Changes in distribution of cystatin C, apolipoprotein E and ferritin in rat hypothalamus after hypophysectomy.

To clarify the mechanism underlying the process of degeneration of injured CNS neurons, we have immunohistochemically examined the distribution of cystatin C, apolipoprotein E, IgG, transferrin and ferritin in the hypophysectomized rat hypothalamus. Stainings for ferritin revealed that reactive microglial cells massed in the paraventricular and supraoptic nuclei 14 days after hypophysectomy, when the degeneration of vasopressin neuronal cell bodies was apparent. Cystatin C-positive magnocellular neurons first appeared at 4 days and the number of intensely-stained cells increased rapidly up to the 7th day of hypophysectomy, followed by a decrease thereafter. Most of such cystatin C-positive neurons were simultaneously stained with anti-vasopressin serum. Accumulation of apolipoprotein E in extracellular spaces was obvious in the both hypothalamic magnocellular nuclei at 7 days. Several apolipoprotein E-positive cells were localized in the supraoptic nucleus, although the number of apolipoprotein E-positive cells was much smaller than that of cystatin C-positive cells. The experiments performed with the transferrin and IgG antibodies showed undetectable levels of such molecules in and around the degenerating magnocellular neurons during whole experimental periods. These findings suggest the importance of cystatin C and apolipoprotein E in the process of degeneration and/or regeneration of magnocellular neurons after hypophysectomy.

Animals↗
PubMed2001

Serum cystatin C concentration as a marker of renal dysfunction in the elderly.

Serum cystatin C is a novel marker of renal function claimed to be superior to plasma creatinine. We assessed both parameters in young normotensive subjects (n = 12; 6 men; mean age, 25 +/- 2 years) and elderly normotensive and hypertensive subjects (n = 41; 19 men; mean age, 67 +/- 6 years). Glomerular filtration rate (GFR) was measured in all individuals using the inulin clearance (C(in)) technique. Compared with young subjects, mean GFR was modestly but significantly (P: < 0.001) less in elderly subjects (young, 119 +/- 11 mL/min/1.73 m(2) versus elderly, 104 +/- 12 mL/min/1.73 m(2)). Mean plasma creatinine concentration was identical in both groups (young, 0.93 +/- 0.11 mg/dL versus elderly, 0.93 +/- 0.10 mg/dL; P: < 0.90). Mean serum cystatin C concentration was significantly (P: < 0.001) greater in elderly subjects (0.84 +/- 0.10 mg/L) compared with young subjects (0.69 +/- 0.08 mg/L). In all but one elderly subject, plasma creatinine concentration was within the 95% confidence interval of plasma creatinine concentration in young subjects. Eleven of 41 elderly subjects (27%) had GFRs less than the lower 95% confidence interval, respectively, and 12 of 41 elderly subjects (29%) had a serum cystatin C concentration greater than the upper 95% confidence interval in young subjects. The correlation between serum cystatin C concentration and C(in) (r = -0.65; P: < 0.001) was considerably better than between plasma creatinine concentration and C(in) (r = -0.30; P: < 0.02). Serum cystatin C concentration is a better marker of renal dysfunction (ie, reduced GFR) than plasma creatinine concentration, at least in elderly subjects with plasma creatinine concentrations within the normal range.

Adult↗
PubMed2001

Serum cystatin C is an independent predictor of total homocysteine levels in stable Korean renal transplant recipients with normal serum creatinine.

OBJECTIVES: To examine the determinants of fasting plasma total homocysteine (tHcy) levels such as cystatin C, serum creatinine (SCr), estimated glomerular filtration rate (GFR) from Cockroft-Gault equation, albumin, plasma folate, vitamin B12, and pyridoxal-5'-phosphate (PLP) among Korean renal transplant recipients (RTR) with normal SCr levels (< or =1.4 mg/dL). DESIGN: Cross-sectional study. SETTING: Nephrology and Transplant Service, Catholic University Kangnam St. Mary's Hospital, Seoul, Korea. PARTICIPANTS: Fifty-one chronic stable Korean RTR with normal SCr levels (< or =1.4 mg/dL) 6 months or more following transplantation. MEASURES: Medical record review, anthropometric measurements, and overnight (10 to 14 hours) fasting blood samples for measurement of plasma tHcy, folate, vitamin B12, PLP, SCr, albumin, and cystatin C. RESULTS: General linear regression model including age, gender, vitamin status, and measurements of renal function showed that cystatin C and folate were independent predictors of tHcy levels. The partial regression coefficient for folate was -0.444 (P <.01) and for cystatin C, it was +0.334 (P <.05). SCr, estimated GFR, vitamin B12, PLP, age, and gender were not independent predictors of tHcy levels in this model. CONCLUSION: Both cystatin C and folate status were major independent determinants of fasting tHcy levels in the subgroup of Korean RTR with normal SCr.

Adult↗
PubMed2001

Three-dimensional domain swapping in the folded and molten-globule states of cystatins, an amyloid-forming structural superfamily.

Cystatins, an amyloid-forming structural superfamily, form highly stable, domain-swapped dimers at physiological protein concentrations. In chicken cystatin, the active monomer is a kinetic trap en route to dimerization, and any changes in solution conditions or mutations that destabilize the folded state shorten the lifetime of the monomeric form. In such circumstances, amyloidogenesis will start from conditions where a domain-swapped dimer is the most prevalent species. Domain swapping occurs by a rearrangement of loop I, generating the new intermonomer interface between strands 2 and 3. The transition state for dimerization has a high level of hydrophobic group exposure, indicating that gross conformational perturbation is required for domain swapping to occur. Dimerization also occurs when chicken cystatin is in its reduced, molten-globule state, implying that the organization of secondary structure in this state mirrors that in the folded state and that domain swapping is not limited to the folded states of proteins. Although the interface between cystatin-fold units is poorly defined for cystatin A, the dimers are the appropriate size to account for the electron-dense regions in amyloid protofilaments.

Amino Acid Sequence↗