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Medicina Clinica Mar 2000
Review
Topics: Angiostatins; Antineoplastic Agents; Humans; Neoplasms; Neovascularization, Pathologic; Neovascularization, Physiologic; Peptide Fragments; Plasminogen
PubMed: 10786363
DOI: 10.1016/s0025-7753(00)71319-4 -
Cell and Tissue Research Feb 2014There is a critical need to identify molecules that modulate the biology of neutrophils because activated neutrophils, though necessary for host defense, cause exuberant...
There is a critical need to identify molecules that modulate the biology of neutrophils because activated neutrophils, though necessary for host defense, cause exuberant tissue damage through production of reactive oxygen species and increased lifespan. Angiostatin, an endogenous anti-angiogenic cleavage product of plasminogen, binds to integrin αvβ3, ATP synthase and angiomotin and its expression is increased in inflammatory conditions. We test the hypothesis that angiostatin inhibits neutrophil activation, induces apoptosis and blocks recruitment in vivo and in vitro. The data show immuno-reactivity for plasminogen/angiostatin in resting neutrophils. Angiostatin conjugated to FITC revealed that angiostatin was endocytozed by activated mouse and human neutrophils in a lipid raft-dependent fashion. Co-immunoprecipitation of human neutrophil lysates, confocal microscopy of isolated mouse and human neutrophils and functional blocking experiments showed that angiostatin complexes with flotillin-1 along with integrin αvβ3 and ATP synthase. Angiostatin inhibited fMLP-induced neutrophil polarization, as well as caused inhibition of hsp-27 phosphorylation and stabilization of microtubules. Angiostatin treatment, before or after LPS-induced neutrophil activation, inhibited phosphorylation of p38 and p44/42 MAPKs, abolished reactive oxygen species production and released the neutrophils from suppressed apoptosis, as indicated by expression of activated caspase-3 and morphological evidence of apoptosis. Finally, intravital microscopy and myeloperoxidase assay showed inhibition of neutrophil recruitment in post-capillary venules of TNFα-treated cremaster muscle in mouse. These in vitro and in vivo data demonstrate angiostatin as a broad deactivator and silencer of neutrophils and an inhibitor of their migration. These data potentially open new avenues for the development of anti-inflammatory drugs.
Topics: Angiostatins; Animals; Apoptosis; CD18 Antigens; Cell Movement; Cell Polarity; Endocytosis; Humans; Inflammation; Lipopolysaccharides; MAP Kinase Signaling System; Membrane Microdomains; Membrane Proteins; Mice; Microtubules; Mitochondria; Muscles; N-Formylmethionine Leucyl-Phenylalanine; Neutrophil Activation; Neutrophil Infiltration; Neutrophils; Oxidation-Reduction; Protein Subunits; Proton-Translocating ATPases; Reactive Oxygen Species; Tumor Necrosis Factor-alpha
PubMed: 24297047
DOI: 10.1007/s00441-013-1753-0 -
BMC Nephrology Apr 2019This study aimed to evaluate the value of urinary angiostatin levels for assessing disease severity and progression of IgA nephropathy (IgAN).
BACKGROUND
This study aimed to evaluate the value of urinary angiostatin levels for assessing disease severity and progression of IgA nephropathy (IgAN).
METHODS
Urinary angiostatin was identified as one of the distinct proteins in samples of patients with IgAN analyzed by Raybiotech protein array, and further confirmed by enzyme-linked immunosorbent assay (ELISA).
RESULTS
Urinary angiostatin levels were significantly higher in IgAN patients than that in healthy controls (HC) subjects and lower than in disease controls (DC) patients. The concentrations of angiostatin in urine normalized to urinary creatinine (angiostatin/Cr) were positively associated with proteinuria level. With advancing chronic kidney disease (CKD) stage, urinary angiostatin/Cr levels were gradually increased. Urinary angiostatin/Cr levels in patients with Lee's grade IV-V were significantly higher than those in Lee's grade I-II and III. We further compared urinary angiostatin/Cr levels by using Oxford classification and found the expression in patients with mesangial proliferative score 1(M1) was significantly higher than that in M0 (P < 0.001). In addition, the levels of urinary angiostatin/Cr in patients with tubular atrophy/interstitial fibrosis score 1(T1) and T2 were significantly higher than those in T0 (P < 0.01, P < 0.001, respectively). After follow-up, renal survival was significantly worse in patients with higher levels of urinary angiostatin (P < 0.05).
CONCLUSIONS
Urinary angiostatin may be a useful novel noninvasive biomarker to evaluate disease severity and progression of IgAN.
Topics: Adult; Angiostatins; Biomarkers; Creatinine; Disease Progression; Female; Glomerulonephritis, IGA; Humans; Kidney Function Tests; Male; Proteinuria; Reproducibility of Results; Severity of Illness Index; Urinalysis
PubMed: 30943905
DOI: 10.1186/s12882-019-1305-2 -
Journal of Oral Science Sep 2020Tissue engineering for fibrocartilage regeneration using mesenchymal stromal cells (MSC) and biomaterial scaffolds is emerging as a promising strategy, but inhibiting...
Tissue engineering for fibrocartilage regeneration using mesenchymal stromal cells (MSC) and biomaterial scaffolds is emerging as a promising strategy, but inhibiting vascularization to prevent endochondral ossification is important to develop stable implants. The objective of this study was to investigate the effect of angiostatin on inhibition of angiogenesis and promotion of chondrogenesis by collagen scaffolds with or without MSC implanted subcutaneously in rats. One scaffold from the following groups was implanted in each animal: Collagen scaffolds only, scaffolds functionalized with angiostatin, scaffolds loaded with MSC and scaffolds functionalized with angiostatin and loaded with MSC. The various scaffolds were harvested after 2 and 8 weeks for histological analysis, Real-time quantitative polymerase chain reaction (RT-qPCR) and immunofluorescence quantification. Results demonstrated significantly decreased expression of inflammatory (interleukin 1 alpha and beta) and angiogenic genes (platelet and endothelial cell adhesion molecule 1) in scaffolds functionalized with angiostatin after 2 weeks in vivo. Histologically, after 8 weeks, the scaffolds with angiostatin had less inflammatory cells and more collagen matrix formation, but no fibrocartilage formation was detected. Thus, although angiostatin suppressed angiogenesis, it did not stimulate ectopic chondrogenesis in tissue engineered constructs in vivo.
Topics: Angiostatins; Animals; Chondrogenesis; Collagen; Mesenchymal Stem Cells; Rats; Tissue Scaffolds
PubMed: 32684573
DOI: 10.2334/josnusd.19-0327 -
Investigative Ophthalmology & Visual... Sep 2016The primate central retina is characterized by an avascular fovea and well-defined perifoveal capillary plexus. Neither blood vessels nor their accompanying astrocytes...
PURPOSE
The primate central retina is characterized by an avascular fovea and well-defined perifoveal capillary plexus. Neither blood vessels nor their accompanying astrocytes enter the fovea during any stage of retinal development; a balance of angiogenic and angiostatic factors probably maintains foveal avascularity throughout life. The aim of this study was to identify potentially angiorepulsive factors involved in the development of the avascular primate retinal fovea.
METHODS
Retinas of newborn, juvenile, and adult Callithrix jacchus and Macaca fascicularis monkeys and control human retinas were studied to determine the localization of angiostatin relative to III β-tubulin, glial fibrillary acidic protein, vascular endothelial growth factor (VEGF), platelet endothelial cell adhesion molecule-1 (PECAM), and the angiostatin receptor αvβ3-integrin in the foveal, macular, and peripheral retina. Expression studies were performed using immunohistochemistry (IHC) on retinal whole-mount and paraffin sections, and Western blotting on frozen material. The complex network of the main retinal cell types was identified by IHC of retinal whole mounts.
RESULTS
In general, lifetime expression of angiostatin was found in all retinas. Colabeling with different markers revealed retinal ganglion cells as the main source of angiostatin expression in the primate retina, whereas PECAM-immunopositive blood capillaries expressed the angiostatin receptor αvβ3-integrin, and capillary-associated astrocytes expressed VEGF.
CONCLUSIONS
This study provides the first evidence of angiostatin expression in the primate retina; the expression of angiostatin in the avascular foveal region and the peripheral retina suggests that angiostatin may play a role in the regulation of retinal vascularization, providing a possible explanation for the development and persistence of an avascular fovea.
Topics: Aged; Angiostatins; Animals; Animals, Newborn; Blotting, Western; Callithrix; Capillaries; Female; Fovea Centralis; Glial Fibrillary Acidic Protein; Humans; Immunohistochemistry; Macaca fascicularis; Male; Middle Aged; Retinal Ganglion Cells; Retinal Vessels
PubMed: 27583825
DOI: 10.1167/iovs.16-19286 -
Oncology Reports 2003Angiostatin is a potent inhibitor of neovascularization, tumor growth and metastasis. We examined the expression of angiostatin and vascular endothelial growth factor...
Angiostatin is a potent inhibitor of neovascularization, tumor growth and metastasis. We examined the expression of angiostatin and vascular endothelial growth factor (VEGF) through immunohistochemical analysis, along with microvessel density, in primary tumors obtained from 55 ovarian carcinoma patients. Angiostatin expression was not related to either stage of disease or histology. However, VEGF expression and microvessel density were related to stage of disease. Angiostatin expression did not correlate with VEGF expression. Microvessel density correlated with VEGF, but not angiostatin expression. Univariate analysis revealed that lack of angiostatin expression, VEGF expression, microvessel density and advanced stage of disease were significant risk factors for reduced survival. Multivariate analysis revealed that lack of angiostatin expression and advanced stage of disease were significant risk factors for reduced survival. Survival time was longer in patients with angiostatin-positive and VEGF-negative tumors than in patients with angiostatin-negative and VEGF-positive tumors. The presence of angiostatin expression and absence of VEGF expression are favorable prognostic factors with regard to survival in ovarian carcinoma patients.
Topics: Angiostatins; Cell Line, Tumor; Female; Humans; Immunohistochemistry; Microcirculation; Multivariate Analysis; Ovarian Neoplasms; Prognosis; Risk Factors; Time Factors; Vascular Endothelial Growth Factor A
PubMed: 12883685
DOI: No ID Found -
Allergy Jun 2023
Topics: Humans; Angiostatins; Angiomotins; Airway Remodeling; Microfilament Proteins; Intercellular Signaling Peptides and Proteins; Asthma; Inflammation; Biomarkers
PubMed: 36602260
DOI: 10.1111/all.15637 -
American Journal of Physiology. Lung... Jan 2014Acute lung injury is marked by profound influx of activated neutrophils, which have delayed apoptosis, along with fluid accumulation that impairs lung function and...
Acute lung injury is marked by profound influx of activated neutrophils, which have delayed apoptosis, along with fluid accumulation that impairs lung function and causes high mortality. Inflammatory and antimicrobial molecules, such as reactive oxygen species from activated neutrophils with prolonged lifespan, cause tissue damage and contribute to lung dysfunction. Angiostatin, an endogenous antiangiogenic molecule, is expressed in the lavage fluid of patients with acute respiratory distress syndrome and modifies neutrophil infiltration in a mouse model of peritonitis. Our aim was to investigate the therapeutic role of angiostatin in acute lung injury. We analyzed bronchoalveolar lavage and lung tissues from C57BL/6 mouse model of Escherichia coli LPS-induced acute lung injury to assess the effects of angiostatin treatment. Subcutaneous angiostatin administered at 5 h after LPS treatment reduces histological signs of inflammation, protein accumulation, lung Gr1+ neutrophils, myeloperoxidase activity, and expression of phosphorylated p38 MAPK in lung tissues and peripheral blood neutrophils, while increasing the number of apoptotic cells in the lungs without affecting the levels of macrophage inflammatory protein-1 α, IL-1β, keratinocyte chemoattractant, and monocyte chemoattractant protein-1 in lavage and lung homogenates at 9 and 24 h after LPS treatment. In contrast, angiostatin administered intravenously 5 h after LPS treatment did not reduce histological sign of inflammation, BAL cell recruitment, and protein concentration at 9 h of LPS treatment. We conclude that angiostatin administered subcutaneously after LPS challenge inhibits acute lung inflammation up to 24 h after LPS treatment.
Topics: Acute Lung Injury; Angiostatins; Animals; Anti-Inflammatory Agents; Apoptosis; Bronchoalveolar Lavage Fluid; Disease Models, Animal; Injections, Subcutaneous; Lipopolysaccharides; Lung; Male; Mice; Mice, Inbred C57BL; Neutrophil Infiltration; Neutrophils; Peroxidase; p38 Mitogen-Activated Protein Kinases
PubMed: 24213918
DOI: 10.1152/ajplung.00368.2012 -
Arthritis Research & Therapy Jan 2018The aim was to study urinary angiostatin, CXC chemokine ligand 4 (CXCL4) and vascular cell adhesion molecule-1 (VCAM-1) as biomarkers of renal disease in systemic lupus...
BACKGROUND
The aim was to study urinary angiostatin, CXC chemokine ligand 4 (CXCL4) and vascular cell adhesion molecule-1 (VCAM-1) as biomarkers of renal disease in systemic lupus erythematosus (SLE).
METHOD
Patients who fulfilled ≥ 4 American College of Rheumatology (ACR) criteria for SLE with active renal, active non-renal or inactive disease, and a group of healthy controls were studied. Urine samples were assayed for angiostatin, CXCL4 and VCAM-1 by ELISA, and normalized by creatinine. Receiver operating characteristic analysis was performed to obtain the best cutoff values to calculate the performance of these markers in differentiating the different groups of patients as compared to anti-double-stranded DNA (anti-dsDNA) and complement C3. Correlation between these urinary biomarkers and various renal parameters was also tested.
RESULTS
Patients with SLE (n = 227; 80 with inactive SLE, 67 with active non-renal disease and 80 with active renal disease; 94% women; age 39.2 ± 13.8 years) and 53 controls (96% women) were studied. All were ethnic Chinese. Urinary angiostatin, CXCL4 and VCAM-1 (normalized for creatinine) were significantly higher in patients with active renal disease than in patients with active non-renal disease, patients with inactive SLE and controls. These markers correlated significantly with total SLE disease activity index (SLEDAI) and renal SLEDAI scores, and with the urinary protein-to-creatinine ratio. Urine angiostatin exhibited higher specificity and sensitivity in differentiating active renal from active non-renal SLE (area under the curve (AUC) 0.87) than serum anti-dsDNA/C3. Urine CXCL4 (AUC 0.64) and VCAM-1 (AUC 0.73), on the other hand, performed similarly to anti-dsDNA/C3. All three markers performed comparably to anti-dsDNA/C3 in distinguishing active from inactive SLE. In a subgroup of 68 patients with paired renal biopsy, the urinary levels of these proteins did not differ significantly between the proliferative and non-proliferative types of lupus nephritis. Urinary CXCL4 and VCAM-1 correlated significantly with the histologic activity score, and urinary angiostatin correlated significantly with proteinuria in this subgroup.
CONCLUSIONS
Urinary angiostatin, CXCL4 and VCAM-1 are potential biomarkers for SLE, in particular lupus nephritis. Further longitudinal studies are necessary to delineate the performance of these markers in predicting renal flares and prognosis in SLE patients.
Topics: Adult; Angiostatins; Biomarkers; Female; Humans; Kidney Function Tests; Lupus Erythematosus, Systemic; Lupus Nephritis; Male; Middle Aged; Platelet Factor 4; Sensitivity and Specificity; Vascular Cell Adhesion Molecule-1; Young Adult
PubMed: 29325582
DOI: 10.1186/s13075-017-1498-3 -
Vascular Pharmacology Apr 2013Angiostatin is an angiogenesis inhibitor in part generated by and released from platelets. Since platelets upon thrombus formation can give rise to areas of hypoxia, we...
Angiostatin is an angiogenesis inhibitor in part generated by and released from platelets. Since platelets upon thrombus formation can give rise to areas of hypoxia, we investigated the effects of angiostatin on endothelial cell migration and apoptosis during hypoxia. Human microvascular endothelial cells (HMVEC-L) were exposed to angiostatin under normoxic or hypoxic conditions. Apoptosis was measured by flow-cytometry. HMVEC-L migration was studied using a modified Boyden Chamber assay, in which migration is MMP-dependent. MMP-2, MMP-14, and VEGF levels were measured using immunoblot, Q-PCR and ELISA. During hypoxia HMVEC-L were protected from angiostatin-induced apoptosis due to increased hypoxia-induced VEGF expression. However, MMP-dependent migration of HMVEC-L was inhibited by angiostatin under hypoxic but not normoxic conditions. Angiostatin decreased MMP-2 at the gene and protein levels only in HMVEC-L exposed to hypoxia. A similar result was obtained for MMP-14. Higher angiostatin concentrations, as would be seen during thrombosis, induced HMVEC-L apoptosis, which was not rescued by VEGF. Under hypoxic conditions angiostatin's primary anti-angiogenic mechanism is likely inhibition of endothelial cell MMP-dependent endothelial cell migration. Only at higher concentrations does angiostatin induce endothelial cell death. This study identifies a novel angiostatin anti-angiogenesis mechanism that is only triggered under pathological-like conditions.
Topics: Angiogenesis Inhibitors; Angiostatins; Apoptosis; Blood Platelets; Cell Hypoxia; Cell Line; Cell Movement; Dose-Response Relationship, Drug; Endothelial Cells; Flow Cytometry; Gene Expression Regulation; Humans; Immunoblotting; Matrix Metalloproteinase 14; Matrix Metalloproteinase 2; Real-Time Polymerase Chain Reaction; Reverse Transcriptase Polymerase Chain Reaction; Thrombosis; Vascular Endothelial Growth Factor A
PubMed: 23220260
DOI: 10.1016/j.vph.2012.11.003