Abstract
Background Atherosclerosis is a multifactorial process. Emerging evidence highlights a role of the enzyme heparanase in various disease states, including atherosclerosis formation and progression. Objective The aim of the study was to investigate the effect of heparanase inhibition on blood pressure, blood glucose levels, and oxidative stress in apoE−/− mice. Methods Male apoE−/− mice were divided into two groups: one treated by the heparanase inhibitor PG545, administered intraperitoneally weekly for seven weeks, and the other serving as control group (injected with saline). Blood pressure was measured a day before sacrificing the animals. Serum glucose levels and lipid profile were measured. Assessment of oxidative stress was performed as well. Results PG545 significantly lowered blood pressure and serum glucose levels in treated mice. It also caused significant reduction of the serum oxidative stress. For safety concerns, liver enzymes were assessed, and PG545 caused significant elevation only of alanine aminotransferase, but not of the other hepatic enzymes. Conclusion Heparanase inhibition by PG545 caused marked reduction of blood pressure, serum glucose levels, and oxidative stress in apolipoprotein E deficient mice, possibly via direct favorable metabolic and hemodynamic changes caused by the inhibitor. Possible hepatotoxic and weight wasting effects are subject for future investigation.
Highlights
Administration of the heparanase inhibitor PG545 resulted in significant reduction in blood pressure
The systolic blood pressure was reduced significantly by 13 mmHg, from 128±16 mmHg in the control group (n = 12) compared to 116±23 mmHg in the study group (n = 12), the diastolic blood pressure by 11 mmHg, 97 ± 13 mmHg in the control group compared to 87 ± 12 in the study group, and the mean blood pressure by 10 mmHg, 107±13 mmHg in the control group compared to 97±20 mmHg in the treatment group, p < 0.001 compared to the control group in the three mentioned parameters (Figure 1)
We reported a major role of heparanase in acute ischemia/reperfusion acute kidney injury in a mouse model, and treating animals with the heparanase inhibitors PG545 and SST0001 was associated with significantly reduced levels of markers of acute kidney injury [33]
Summary
The aim of the study was to investigate the effect of heparanase inhibition on blood pressure, blood glucose levels, and oxidative stress in apoE−/− mice. PG545 significantly lowered blood pressure and serum glucose levels in treated mice. It caused significant reduction of the serum oxidative stress. Heparanase inhibition by PG545 caused marked reduction of blood pressure, serum glucose levels, and oxidative stress in apolipoprotein E deficient mice, possibly via direct favorable metabolic and hemodynamic changes caused by the inhibitor. Different modifications in the protein skeleton and in the disaccharide chains are responsible for the wide variety of the HSPGs, which are characterized from each
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