Thromboxane A(2) (TXA(2)) is a potent prothrombotic and immune modulating
lipid mediator, which is implicated in
cardiovascular diseases, in particular, atherosclerotic lesion development and thrombogenicity. Here, we tested the hypothesis that
thromboxane synthase (TXAS), the obligate
enzyme required to synthesize TXA(2), is expressed within the human atherosclerotic lesion, thus potentially contributing to TXA(2) synthesis and disease development. In an animal study, different
atherosclerosis-prone mouse strains were investigated and compared with control mice. In a patient study (n = 134),
endarterectomies of carotid atherosclerotic lesions were compared with non-atherosclerotic arteries (n = 11). Expression of TXAS was evaluated by real-time quantitative reverse transcription PCR and immunohistochemistry. TXAS
mRNA expression was increased within the vascular wall in mouse models of
atherosclerosis with advanced lesions. In humans, TXAS was expressed in the atherosclerotic lesion, associated with increased inflammatory cells, in particular M2 polarized macrophages, and increased in atherosclerotic lesions of patients with recent symptoms of thrombotic events. Production of TXA(2) by plaque tissue, verified by gas chromatography-mass spectrometry, increased after addition of
arachidonic acid or
lipopolysaccharide, and was inhibited by the TXAS inhibitor
furegrelate. The findings suggest that intraplaque TXA(2) generation may contribute to the development of
atherosclerosis and its thrombotic complications in humans.