Thromboxane A2 (TXA2) 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 TXA2 metabolite, TXB2, was lower in both
aspirin- and nstpbp5185-treated mice, while the urinary 2,3-dinor-6-keto PGF1α (a PGI2 metabolite) and plasma iPF2α-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.