The Thromboxane Receptor Antagonist S18886 but Not Aspirin Inhibits Atherogenesis in Apo E–Deficient Mice

Abstract

Abstract-Atherosclerosis involves a complex array of factors, including leukocyte adhesion and platelet vasoactive factors. Aspirin, which is used to prevent secondary complications of atherosclerosis, inhibits platelet production of thromboxane (Tx) A 2 . The actions of TxA 2 as well as of other arachidonic acid products, such as prostaglandin (PG) H 2 , PGF 2␣ , hydroxyeicosatetraenoic acids, and isoprostanes, can be effectively antagonized by blocking thromboxane (TP) receptors. The purpose of this study was to determine the role of platelet-derived TxA 2 in atherosclerotic lesion development by comparing the effects of aspirin and the TP receptor antagonist S18886. The effect of 11 weeks of treatment with aspirin (30 mg ⅐ kgon aortic root atherosclerotic lesions, serum levels of intercellular adhesion molecule-1 (ICAM-1), and the TxA 2 metabolite TxB 2 was determined in apolipoprotein E-deficient mice at 21 weeks of age. Both treatments did not affect body or heart weight or serum cholesterol levels. Aspirin, to a greater extent than S18886, significantly decreased serum TxB 2 levels, indicating the greater efficacy of aspirin in preventing platelet synthesis of TxA 2 . S18886, but not aspirin, significantly decreased aortic root lesions as well as serum ICAM-1 levels. S18886 also prevented the increased expression of ICAM-1 in cultured human endothelial cells stimulated by the TP receptor agonist U46619. These results indicate that inhibition of platelet TxA 2 synthesis with aspirin has no significant effect on atherogenesis or adhesion molecule levels. The effects of S18886 suggest that blockade of TP receptors inhibits atherosclerosis by a mechanism independent of platelet-derived TxA 2 , perhaps by preventing the expression of adhesion molecules whose expression is stimulated by eicosanoids other than TxA 2 .

Characterization of isoprostane signaling: Evidence for a unique coordination profile of 8-iso-PGF2α with the thromboxane A2 receptor, and activation of a separate cAMP-dependent inhibitory pathway in human platelets

“…For example, results obtained with an in vivo mouse model suggested that isoprostanes participate in thrombus development at sites of vascular injury [5]. Other studies found that the levels of isoprostanes become elevated in patients with atherosclerosis [6], acute myocardial infarction [7], as well as in a canine model of ischemia-reperfusion injury [7].…”

Investigation of a Thromboxane A 2 Receptor–Based Vaccine for Managing Thrombogenesis

“…Although vaccine development is a complex and challenging process, peptide‐based vaccines (eg, C‐EL2) provide several advantages in comparison to conventional vaccines 12, 59. Peptide vaccines are safer and more economic,12, 59 when compared with traditional vaccines that are made of dead or attenuated pathogens,3 inactivated toxins, and recombinant subunits.…”

“…Peptide vaccines are safer and more economic,12, 59 when compared with traditional vaccines that are made of dead or attenuated pathogens,3 inactivated toxins, and recombinant subunits. Peptide vaccine production is also relatively inexpensive because of the ease of production and simplistic composition 12, 59.…”

“…Peptide vaccines are safer and more economic,12, 59 when compared with traditional vaccines that are made of dead or attenuated pathogens,3 inactivated toxins, and recombinant subunits. Peptide vaccine production is also relatively inexpensive because of the ease of production and simplistic composition 12, 59. In addition, peptide vaccines avoid the inclusion of unnecessary components possessing high reactogenicity to the host, such as lipopolysaccharides, lipids, or toxins 12, 59.…”

“…Peptide vaccine production is also relatively inexpensive because of the ease of production and simplistic composition 12, 59. In addition, peptide vaccines avoid the inclusion of unnecessary components possessing high reactogenicity to the host, such as lipopolysaccharides, lipids, or toxins 12, 59. Vaccination‐based approaches for targeting G‐protein–coupled receptors have been gaining much attention recently,70 and recent clinical trials supported the effectiveness of a cocaine dependence vaccine71 and an angiotensin II–based vaccine (in hypertensive patients),72 as well as their safety for humans.…”