Blockade of Vascular Smooth Muscle Cell Proliferation and Intimal Thickening After Balloon Injury by the Sulfated Oligosaccharide PI-88

Francis, Douglas J.; Parish, Christopher R.; McGarry, Mark; Santiago, Fernando S.; Lowe, Harry C.; Brown, Kathryn J.; Bingley, John; Hayward, Ian Philip; Cowden, W. B.; Campbell, Julie H.; Campbell, Gordon; Chesterman, Colin N.; Khachigian, Levon M.

doi:10.1161/01.res.0000071345.76095.07

Cited by 55 publications

(41 citation statements)

References 33 publications

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“…At present, it is not clear which of these possibilities could account for this observation. It is known that FGF is abundant in the GBM (39) and that PI-88 directly binds to FGF and renders it biologically inactive (27). This known effect of PI-88 may contribute to abnormal GBM biosynthesis.…”

Section: Discussionmentioning

confidence: 99%

“…Furthermore, PI-88 binds and inactivates FGF (27). Podocytes have been shown to release FGF in response to injury in PHN, and FGF administration augments podocyte injury (11).…”

Section: Discussionmentioning

confidence: 99%

“…Furthermore, recent studies have demonstrated that PI-88 directly binds to FGF-1, FGF-2, and VEGF. In addition, FGF-2 binding by PI-88 renders it biologically inactive (26,27). PI-88 has been likened to a heparan sulfate mimetic acting by simply sequestering released growth factors and rendering them biologically inactive (28).…”

mentioning

confidence: 99%

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A Synthetic Heparanase Inhibitor Reduces Proteinuria in Passive Heymann Nephritis

Levidiotis

Freeman

Punler³

et al. 2004

Journal of the American Society of Nephrology

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Abstract. The ␤-D-endoglycosidase heparanase has been proposed to be important in the pathogenesis of proteinuria by acting to selectively degrade the negatively charged side chains of heparan sulfate proteoglycans (HSPG) within the glomerular basement membrane (GBM). A loss of the negatively charged HSPG may result in alteration of the permselective properties of the GBM, loss of glomerular epithelial and endothelial cell anchor points, and liberation of growth factors. This study examined the effect of PI-88, a sulfated oligosaccharide heparanase inhibitor, on renal function, glomerular ultrastructure, and proteinuria. Continuous PI-88 infusion at 25 mg/kg per d did not adversely affect animal behavior, growth, or GFR. Cortical tubular vacuolation, however, was observed by light microscopy, and GBM thickness was significantly reduced in these animals (P Ͻ 0.0002). Tissue distribution studies using [35 S]-labeled PI-88 revealed high levels of radioactivity in the kidney after a single subcutaneous injection of 25 mg/kg, suggesting protracted accumulation; moreover, active PI-88 was detected in urine. In passive Heymann nephritis, PI-88 delivered as a continuous infusion at 25 mg/kg per d significantly reduced autologous-phase proteinuria, at day 14 (P Ͻ 0.009), in the absence of altered sheep antibody deposition, C5b-9 deposition, and circulating rat anti-sheep antibody titers. Glomerular vascular endothelial growth factor and fibroblast growth factor expression was unaffected by PI-88 administration. However, PI-88 administration significantly prevented glomerular HSPG loss as demonstrated by quantitative immunofluorescence studies (P Ͻ 0.0001) in the absence of altered agrin distribution. These data therefore confirm the importance of heparanase in the development of proteinuria.

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Section: Discussionmentioning

confidence: 99%

“…Furthermore, PI-88 binds and inactivates FGF (27). Podocytes have been shown to release FGF in response to injury in PHN, and FGF administration augments podocyte injury (11).…”

Section: Discussionmentioning

confidence: 99%

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A Synthetic Heparanase Inhibitor Reduces Proteinuria in Passive Heymann Nephritis

Levidiotis

Freeman

Punler³

et al. 2004

Journal of the American Society of Nephrology

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“…Flow cytometric analysis Cells were starved of glucose overnight and then incubated for 48 h in the medium containing 5 or 30 mmol/l glucose or the indicated concentrations of H 2 O 2 in the absence or presence of three HPR1 inhibitors, PI-88, heparin and sulodexide (50 μg/ml each) [28]. Cell surface heparan sulphate was stained with an anti-heparan sulphate monoclonal antibody (clone HepSS) according to previous publications [18].…”

Section: Methodsmentioning

confidence: 99%

Reactive oxygen species mediate high glucose-induced heparanase-1 production and heparan sulphate proteoglycan degradation in human and rat endothelial cells: a potential role in the pathogenesis of atherosclerosis

et al. 2011

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Aims/hypothesis The content of heparan sulphate is reduced in the endothelium under hyperglycaemic conditions and may contribute to the pathogenesis of atherosclerosis. Heparanase-1 (HPR1) specifically degrades heparan sulphate proteoglycans. We therefore sought to determine whether: (1) heparan sulphate reduction in endothelial cells is due to increased HPR1 production through increased reactive oxygen species (ROS) production; and (2) HPR1 production is increased in vivo in endothelial cells under hyperglycaemic and/or atherosclerotic conditions. Methods HPR1 mRNA and protein levels in endothelial cells were analysed by RT-PCR and Western blot or HPR1 enzymatic activity assay, respectively. Cell surface heparan sulphate levels were analysed by FACS. HPR1 in the artery from control rats and a rat model of diabetes, and from patients under hyperglycaemic and/or atherosclerotic conditions was immunohistochemically examined. Results High-glucose-induced HPR1 production and heparan sulphate degradation in three human endothelial cell lines, both of which were blocked by ROS scavengers, glutathione and N-acetylcysteine. Exogenous H 2 O 2 induced HPR1 production, subsequently leading to decreased cell surface heparan sulphate levels. HPR1 content was significantly increased in endothelial cells in the arterial walls of a rat model of diabetes. Clinical studies revealed that HPR1 production was increased in endothelial cells under hyperglycaemic conditions, and in endothelial cells and macrophages in atherosclerotic lesions.

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“…A note of caution could be raised with regard to the therapeutic use of sulfated oligosaccharides in general and JG3 in particular, in that a large body of literature has documented the capability of heparin and other sulfated oligosaccharides to facilitate (as opposed to inhibit) growth factor release. Notably, in one recent study, PI-88 was also observed to enhance release of the heparan sulfate binding growth factor bFGF, and yet PI-88 inhibited bFGF-mediated cell signaling (34). However, modified heparin by glycol-splitting as N-acetylheparins failed otherwise to release bFGF from extracellular matrix and, thus, its mitogenic activity (35).…”

Section: Discussionmentioning

confidence: 99%

Oligomannurarate Sulfate, a Novel Heparanase Inhibitor Simultaneously Targeting Basic Fibroblast Growth Factor, Combats Tumor Angiogenesis and Metastasis

Zhao

Liu²,

Chen³

et al. 2006

Cancer Research

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Inhibitors of tumor angiogenesis and metastasis are increasingly emerging as promising agents for cancer therapy. Recently, heparanase inhibitors have offered a new avenue for such work because heparanase is thought to be critically involved in the metastatic and angiogenic potentials of tumor cells. Here, we report that oligomannurarate sulfate (JG3), a novel marine-derived oligosaccharide, acts as a heparanase inhibitor. Our results revealed that JG3 significantly inhibited tumor angiogenesis and metastasis, both in vitro and in vivo, by combating heparanase activity via binding to the KKDC and QPLK domains of the heparanase molecule. The JG3-heparanase interaction was competitively inhibited by low molecular weight heparin (4,000 Da) but not by other glycosaminoglycans. In addition, JG3 abolished heparanasedriven invasion, inhibited the release of heparan sulfatesequestered basic fibroblast growth factor (bFGF) from the extracellular matrix, and repressed subsequent angiogenesis. Moreover, JG3 inactivated bFGF-induced bFGF receptor and extracellular signal-regulated kinase 1/2 phosphorylation and blocked bFGF-triggered angiogenic events by directly binding to bFGF. Thus, JG3 seems to inhibit both major heparanase activities by simultaneously acting as a substrate mimetic and as a competitive inhibitor of heparan sulfate. These findings suggest that JG3 should be considered as a promising candidate agent for cancer therapy. (Cancer Res 2006; 66(17): 8779-87)

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Blockade of Vascular Smooth Muscle Cell Proliferation and Intimal Thickening After Balloon Injury by the Sulfated Oligosaccharide PI-88

Cited by 55 publications

References 33 publications

A Synthetic Heparanase Inhibitor Reduces Proteinuria in Passive Heymann Nephritis

A Synthetic Heparanase Inhibitor Reduces Proteinuria in Passive Heymann Nephritis

Reactive oxygen species mediate high glucose-induced heparanase-1 production and heparan sulphate proteoglycan degradation in human and rat endothelial cells: a potential role in the pathogenesis of atherosclerosis

Oligomannurarate Sulfate, a Novel Heparanase Inhibitor Simultaneously Targeting Basic Fibroblast Growth Factor, Combats Tumor Angiogenesis and Metastasis

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