pg-545 and Atherosclerosis

Increased oxidative stress is associated with accelerated atherosclerosis. Emerging evidence highlights the role of heparanase in atherogenesis, where heparanase inhibitor PG545 reduces oxidative stress in apolipoprotein E deficient mice (E. Blood pressure decreased in mice treated with low, but not high dose of PG545. In addition, heparanase inhibition caused a dose-dependent reduction in serum oxidative stress, total cholesterol, low-density lipoproteins, triglycerides, high-density lipoproteins, and aryl esterase activity. Although food intake was not reduced by PG545, body weight gain was significantly attenuated in PG545 treated groups. Both doses of PG545 caused a marked reduction in aortic wall thickness and atherosclerosis development, and liver steatosis. Liver enzymes and serum creatinine were not affected by PG545.. Heparanase inhibition by PG545 caused a significant reduction in lipid profile and serum oxidative stress along with attenuation of atherosclerosis, aortic wall thickness, and liver steatosis. Moreover, PG545 attenuated weight gain without reducing food intake. Collectively, these findings suggest that heparanase blockade is highly effective in slowing atherosclerosis formation and progression, and decreasing liver steatosis.

Topics: Animals; Aorta; Aortic Diseases; Atherosclerosis; Blood Pressure; Disease Models, Animal; Disease Progression; Fatty Liver; Glucuronidase; Glycoside Hydrolase Inhibitors; Lipids; Liver; Male; Mice, Knockout, ApoE; Oxidative Stress; Plaque, Atherosclerotic; Saponins

Atherosclerosis is a multifactorial process. Emerging evidence highlights a role of the enzyme heparanase in various disease states, including atherosclerosis formation and progression.. 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.. 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.. 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.. 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.

Topics: Animals; Apolipoproteins E; Atherosclerosis; Blood Glucose; Blood Pressure; Glucose; Glucuronidase; Lipids; Liver; Male; Mice; Mice, Knockout; Oxidative Stress; Saponins