Heparanase Inhibition Reduces Glucose Levels, Blood Pressure, and Oxidative Stress in Apolipoprotein E Knockout Mice

Hamoud, Shadi; Muhammad, Rabia Shekh; Abu-Saleh, Niroz; Hassan, Ahmad; Zohar, Yaniv; Hayek, Tony

doi:10.1155/2017/7357495

Cited by 17 publications

(13 citation statements)

References 58 publications

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“…Under these conditions, the animals likely developed insulin resistance (T2D), which will augment hepatic VLDL output and decrease clearance via both HSPG-dependent and HSPG-independent mechanisms [63–65]. Interestingly administration of the heparanase inhibitor, PG545, to chow-fed Apoe −/− mice reduced plasma glucose levels but had no significant impact on plasma triglyceride levels [70]. Whether PG545 impacts plasma triglyceride metabolism in animals fed a high-fat diet is unknown.…”

Section: Hepatic Heparan Sulfate Contributes To Trl Catabolismmentioning

confidence: 99%

The heparan sulfate proteoglycan grip on hyperlipidemia and atherosclerosis

Gordts

2018

Matrix Biology

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Heparan sulfate proteoglycans are found at the cell surface and in the extracellular matrix, where they interact with a plethora of proteins involved in lipid homeostasis and inflammation. Over the last decade, new insights have emerged regarding the mechanism and biological significance of these interactions in the context of cardiovascular disease. The majority of cardiovascular disease-related deaths are caused by complications of atherosclerosis, a disease that results in narrowing of the arterial lumen, thereby reducing blood flow to critical levels in vital organs, such as the heart and brain. Here, we discuss novel insights into how heparan sulfate proteoglycans modulate risk factors such as hyperlipidemia and inflammation that drive the initiation and progression of atherosclerotic plaques to their clinical critical endpoint.

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Section: Hepatic Heparan Sulfate Contributes To Trl Catabolismmentioning

confidence: 99%

The heparan sulfate proteoglycan grip on hyperlipidemia and atherosclerosis

Gordts

2018

Matrix Biology

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“…HPSE affects glucose metabolism in several disease settings, which could suggest a similar role in cancer. The inhibition of HPSE in the apolipoprotein-E-deficient mouse model of atherosclerosis resulted in a marked reduction of serum glucose levels [ 304 ]. In type-2 diabetes mellitus patients, urine HPSE was shown to correlate with high blood glucose levels, indicating glucose-mediated HPSE expression and secretion, with follow up in vitro studies showing insulin-mediated HPSE secretion by human embryonic kidney cells in culture [ 305 ].…”

Section: Introductionmentioning

confidence: 99%

Heparanase and the hallmarks of cancer

Jayatilleke

Hulett

2020

J Transl Med

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Heparanase is the only mammalian enzyme that cleaves heparan sulphate, an important component of the extracellular matrix. This leads to the remodelling of the extracellular matrix, whilst liberating growth factors and cytokines bound to heparan sulphate. This in turn promotes both physiological and pathological processes such as angiogenesis, immune cell migration, inflammation, wound healing and metastasis. Furthermore, heparanase exhibits non-enzymatic actions in cell signalling and in regulating gene expression. Cancer is underpinned by key characteristic features that promote malignant growth and disease progression, collectively termed the ‘hallmarks of cancer’. Essentially, all cancers examined to date have been reported to overexpress heparanase, leading to enhanced tumour growth and metastasis with concomitant poor patient survival. With its multiple roles within the tumour microenvironment, heparanase has been demonstrated to regulate each of these hallmark features, in turn highlighting the need for heparanase-targeted therapies. However, recent discoveries which demonstrated that heparanase can also regulate vital anti-tumour mechanisms have cast doubt on this approach. This review will explore the myriad ways by which heparanase functions as a key regulator of the hallmarks of cancer and will highlight its role as a major component within the tumour microenvironment. The dual role of heparanase within the tumour microenvironment, however, emphasises the need for further investigation into defining its precise mechanism of action in different cancer settings.

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“…During this study, it was first noted that, the PG545 treatment to both mock- and RRV-infected mice groups caused a reduction in weight gain across the treated groups. Other comparable murine studies of PG545 administration have also reported weight losses in treated animals [30].…”

Section: Discussionmentioning

confidence: 86%

PG545 treatment reduces RRV-induced elevations of AST, ALT with secondary lymphoid organ alterations in C57BL/6 mice

et al. 2019

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Recently the anti-viral effects of prophylactic treatment with the low-molecular-weight heparan sulfate mimetic PG545 in Ross River virus (RRV) infected mice were reported. We further investigated the related, transient pathophysiology of PG545 drug treatment in RRV-infected and mock-infected PG545-treated mice. PG545 treatment resulted in mild lethargy and piloerection, on days after the drug administration. Mice were treated with two or three doses of PG545 within a ten-day period and were subsequently culled at peak disease or at disease resolution. The treatment responses of the spleen and liver were assessed through histology, flow cytometry, gene arrays and serum biochemistry. Microscopy showed an expanded red pulp in the spleen following either two or three treatments with PG545. The red pulp expansion was further demonstrated by the proliferation of megakaryocytes and erythrocyte precursors within the spleen. In addition, flow cytometry and gene array analyses revealed a reduction of lymphocytes within the spleens of PG545-treated mice. Previously unreported, RRV-induced elevations of aspartate aminotransferase (AST) and alanine transaminase (ALT) enzymes and creatinine were also noted in the RRV-infected mice. However, PG545 only reduced AST and ALT levels but not the creatinine levels in infected mice during treatment. Mice treated with three doses of PG545 also showed hepatosplenomegaly and anaemia, which were reversed upon discontinuation of the treatment. In summary, this study demonstrates that dose and frequency related haemopoietic pathophysiology such as hepatosplenomegaly and anaemia, occurred in C57BL/6 mice treated with PG545. However, this effect was reversible once drug administration is terminated.

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Heparanase Inhibition Reduces Glucose Levels, Blood Pressure, and Oxidative Stress in Apolipoprotein E Knockout Mice

Cited by 17 publications

References 58 publications

The heparan sulfate proteoglycan grip on hyperlipidemia and atherosclerosis

The heparan sulfate proteoglycan grip on hyperlipidemia and atherosclerosis

Heparanase and the hallmarks of cancer

PG545 treatment reduces RRV-induced elevations of AST, ALT with secondary lymphoid organ alterations in C57BL/6 mice

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