Long-Term Administration of Highly Purified Eicosapentaenoic Acid Ethyl Ester Improves Blood Coagulation Abnormalities and Dysfunction of Vascular Endothelial Cells in Otsuka Long-Evans Tokushima Fatty Rats

Abstract

Abstract. We investigated the effect of highly purified eicosapentaenoic acid ethyl ester (EPA-E) on blood coagulation abnormalities and dysfunction of vascular endothelial cells in spontaneously diabetic Otsuka Long-Evans Tokushima Fatty rats. The animals were treated with either EPA-E or lard at a daily dose of 0.3 g/kg/day for 52 weeks by gavage, and their coagulation/fibrinolytic parameters, platelet aggregation, and functions of the vascular endothelial cells were examined. EPA-E significantly improved coagulation-related parameters including prothrombin time, activated partial thromboplastin time, fibrinogen level, and activities of factor II, V, VII, VIII, IX, X, XI, and XII, and antithrombin III, and fibrinolysis-related parameters including plasminogen, tissue-type plasminogen activator, a 2 -plasmin inhibitor, and plasminogen activator inhibitor. It also suppressed ADP-or collagen-induced platelet aggregation and the cholesterol/ phospholipid molar ratio in platelet membranes at a dose of 0.3 g/kg. In addition, it significantly increased the migration activity of vascular endothelial cells, and decreased the binding of vascular endothelial cells to vascular endothelial growth factor. In contrast, lard had no effect on hypercoagulation, hypofibrinolysis, and platelet hyperaggregation but significantly aggravated the dysfunction of vascular endothelial cells. These data demonstrate that EPA-E beneficially altered certain factors known to promote thrombosis and atherosclerosis in this animal model. WE reported previously that the long-term administration of highly purified eicosapentaenoic acid ethyl ester (EPA-E), an n-3 polyunsaturated fatty acid, which has an inhibitory effect on platelet aggregation and lipid-lowering effect, causes an improvement of insulin resistance in Otsuka Long-Evans Tokushima Fatty (OLETF) rats, a model of spontaneous noninsulin-dependent diabetes mellitus with obesity [1] and that of high sucrose-induced insulin resistance in Dahl salt-sensitive (Dahl-S) rats [2]. It is well recognized that hyperglycemia enhances many risk factors for arteriosclerosis and works as a thrombus-forming factor via causing blood coagulation abnormalities and dysfunction of vascular endothelial cells and thrombocytes [3,4]. Thus, in the present study, we investigated the effect of EPA-E on blood coagulation abnormalities and

Effects of Eicosapentaenoic Acid on Endothelial Cell-Derived Microparticles, Angiopoietins and Adiponectin in Patients with Type 2 Diabetes

“…Thus, the increase of adiponectin by EPA may exert a platelet-inhibitory effect via nitric oxide. EPA has been reported to play a role in coronary events in hyperlipidemic patients 27) , and its biological functions include the reduction of platelet activation 25,48) , endothelial factors [49][50][51] , and inflammatory markers in metabolic syndrome 52) . Our results suggest that EPA possesses multifunctional anti-thrombotic properties, and that its action is dependent on adiponectin.…”

A review of omega-3 ethyl esters for cardiovascular prevention and treatment of increased blood triglyceride levels

“…As compared with safflower oil feeding, EPA-fed diabetes-prone rats were leaner, had lower blood lipid levels, and a blunted insulin response to glucose testing ( Minami et al 2002 ). Another study in the same rat model found platelet response to ADP and collagen reduced, and a number of coagulation and fibrinolysis parameters altered towards a less procoagulatory state ( Mori, Nobukata, et al 2003 ). Also, migration activity of vascular endothelial cells was increased, and binding of vascular endothelial cells to vascular endothelial cell growth factor decreased ( Mori, Nobukata, et al 2003 ).…”

Models to Study Atherosclerosis: A Mechanistic Insight

“…The effect of hormonal regulation on hemodynamic parameters and atherosclerotic risk factors have also been assessed in womens taking progestin containing contraceptives [606], and testosterone treated rabbit model [609]. Besides this many animal models of thrombosis are also available which can be used to assess the hypercoaguability and thrombogenecity of blood under hyperlipidemic conditions in the presence and absence of test compounds [339,340,445,[610][611][612].…”