Inhibitory Effects of an Orally Active Thromboxane A2 Receptor Antagonist, nstpbp5185, on Atherosclerosis in ApoE-Deficient Mice
Journal
Thrombosis and Haemostasis
Journal Volume
118
Journal Issue
2
Pages
401-414
Date Issued
2018
Author(s)
Abstract
Thromboxane A 2 (TXA 2 ) activation of TP receptor has been shown contributing to the progression and acute complications of atherosclerosis including endothelial dysfunction, platelet hyperactivity and inflammation. Growing evidence suggests that TP receptor may represent as a therapeutic target in atherosclerosis and related cardiovascular diseases. We investigated whether nstpbp5185, an orally active TP receptor antagonist, exhibits protective effects against atherosclerotic progression. Nstpbp5185 and aspirin were orally administered daily for 12 weeks in high-cholesterol-fed ApoE-deficient mice to examine their anti-atherosclerosis effects. Total cholesterol, low-density lipoprotein cholesterol and triglycerides were slightly decreased in nstpbp5185-treated mice. However, nstpbp5185 significantly reduced neointima formation and aortic atherosclerotic lesion area. Nstpbp5185 increased serum paraoxonase 1 activity. In contrast, plasma levels of interleukin-6 and tumour necrosis factor-α were reduced in nstpbp5185-treated mice. Plasma level of TXA 2 metabolite, TXB 2 , was lower in both aspirin- and nstpbp5185-treated mice, while the urinary 2,3-dinor-6-keto PGF 1α (a PGI 2 metabolite) and plasma iPF 2α -III were not altered. Moreover, nstpbp5185 neither caused gastric ulceration nor affected the haemostatic response. Nstpbp5185 also inhibited U46619-induced endothelial NF-kB activation, ICAM-1 and VCAM-1 expression, as well as monocyte adhesion to endothelial cells. In conclusion, nstpbp5185 may represent as an ideal, safe and efficacious agent for preventing atherosclerotic progression through its antiplatelet, anti-inflammatory and antioxidative activities. ? 2017 Schattauer.
Subjects
ApoE-deficient mice; atherosclerosis; thromboxane A 2; TP antagonist
SDGs
Other Subjects
15 hydroxy 11alpha,9alpha epoxymethanoprosta 5,13 dienoic acid; 2,3 dinor 6 oxoprostaglandin F1 alpha; acetylsalicylic acid; alanine aminotransferase; aryldialkylphosphatase 1; aspartate aminotransferase; C reactive protein; creatinine; high density lipoprotein cholesterol; immunoglobulin enhancer binding protein; intercellular adhesion molecule 1; interleukin 6; low density lipoprotein cholesterol; nstpbp 5185; reactive oxygen metabolite; RhoA guanine nucleotide binding protein; thromboxane A2; thromboxane A2 receptor blocking agent; thromboxane B2; triacylglycerol; tumor necrosis factor; unclassified drug; vascular cell adhesion molecule 1; 1-benzyl-2-(5-methyl-2-furyl)benzimidazole; 15 hydroxy 11alpha,9alpha epoxymethanoprosta 5,13 dienoic acid; benzimidazole derivative; reactive oxygen metabolite; thromboxane A2 receptor; animal experiment; animal model; animal tissue; apolipoprotein E knockout mouse; Article; atherosclerosis; biochemical analysis; bleeding time; blood vessel injury; body weight; cell adhesion; cell adhesion assay; cell viability; cholesterol blood level; controlled study; cytokine production; disease exacerbation; drug dose comparison; drug mechanism; enzyme activity; enzyme immunoassay; enzyme linked immunosorbent assay; genetic transfection; heart weight; human; human cell; HUVEC cell line; immunoblotting; male; monocyte; mouse; MTT assay; neointima; nonhuman; priority journal; protein degradation; protein expression; protein phosphorylation; stomach ulcer; vascular endothelium; animal; antagonists and inhibitors; aorta; atherosclerosis; C57BL mouse; cell survival; genetics; metabolism; umbilical vein endothelial cell; 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; Animals; Aorta; Atherosclerosis; Benzimidazoles; Cell Adhesion; Cell Survival; Human Umbilical Vein Endothelial Cells; Humans; Male; Mice; Mice, Inbred C57BL; Mice, Knockout, ApoE; Reactive Oxygen Species; Receptors, Thromboxane A2, Prostaglandin H2
Type
journal article