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Heparanase inhibition attenuates atherosclerosis progression and liver steatosis in E 0 mice.
- Source :
-
Atherosclerosis [Atherosclerosis] 2018 Sep; Vol. 276, pp. 155-162. Date of Electronic Publication: 2018 Jul 24. - Publication Year :
- 2018
-
Abstract
- Background and Aims: 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 <subscript>0</subscript> mice). Herein, we studied the effects of PG545 on atherosclerosis progression in E <subscript>0</subscript> mice.<br />Methods: Male E <subscript>0</subscript> mice fed a high-fat diet (n = 20) were divided into 3 groups treated with weekly intraperitoneal injections of either low (0.2 mg/mouse) or high dose (0.4 mg/mouse)PG545 or normal saline (controls) for twelve weeks. Body weight and food intake were measured weekly. At the end of the treatment period, blood pressure was measured, animals were sacrificed and serum samples were collected and assessed for biochemical parameters and oxidative stress. Aortic vessels and livers were collected for atherosclerotic plaques and histopathological analysis, respectively.<br />Results: 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.<br />Conclusions: 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.<br /> (Copyright © 2018 Elsevier B.V. All rights reserved.)
- Subjects :
- Animals
Aorta enzymology
Aorta pathology
Aortic Diseases enzymology
Aortic Diseases genetics
Aortic Diseases pathology
Atherosclerosis enzymology
Atherosclerosis genetics
Atherosclerosis pathology
Blood Pressure drug effects
Disease Models, Animal
Disease Progression
Fatty Liver enzymology
Fatty Liver genetics
Fatty Liver pathology
Glucuronidase metabolism
Lipids blood
Liver enzymology
Liver pathology
Male
Mice, Knockout, ApoE
Oxidative Stress drug effects
Plaque, Atherosclerotic
Aorta drug effects
Aortic Diseases prevention & control
Atherosclerosis prevention & control
Fatty Liver prevention & control
Glucuronidase antagonists & inhibitors
Glycoside Hydrolase Inhibitors pharmacology
Liver drug effects
Saponins pharmacology
Subjects
Details
- Language :
- English
- ISSN :
- 1879-1484
- Volume :
- 276
- Database :
- MEDLINE
- Journal :
- Atherosclerosis
- Publication Type :
- Academic Journal
- Accession number :
- 30075439
- Full Text :
- https://doi.org/10.1016/j.atherosclerosis.2018.07.026