Thromboxane synthase expression and thromboxane A2 production in the atherosclerotic lesion.
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.
Gabrielsen
Anders
A
Center for Molecular Medicine, Department of Medicine, Karolinska Institutet, Stockholm, Sweden. anders.gabrielsen@cmm.ki.se
Qiu
Hong
H
Bäck
Magnus
M
Hamberg
Mats
M
Hemdahl
Anne-Louise
AL
Agardh
Hanna
H
Folkersen
Lasse
L
Swedenborg
Jesper
J
Hedin
Ulf
U
Paulsson-Berne
Gabrielle
G
Haeggström
Jesper Z
JZ
Hansson
Göran K
GK
D000818:Animals; D050197:Atherosclerosis / Q000201:enzymology* / Q000473:pathology*; D005260:Female; D015870:Gene Expression; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D012333:RNA, Messenger / Q000235:genetics; D013928:Thromboxane A2 / Q000378:metabolism*; D013930:Thromboxane-A Synthase / Q000235:genetics* / Q000378:metabolism
D012333:RNA, Messenger; D013928:Thromboxane A2; D013930:Thromboxane-A Synthase
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