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Thromboxane A synthase-independent production of 12-hydroxyheptadecatrienoic acid, a BLT2 ligand.

ABSTRACT: 12(S)-hydroxyheptadeca-5Z,8E,10E-trienoic acid (12-HHT) has long been considered a by-product of thromboxane A? (TxA?) biosynthesis with no biological activity. Recently, we reported 12-HHT to be an endogenous ligand for BLT2, a low-affinity leukotriene B4 receptor. To delineate the biosynthetic pathway of 12-HHT, we established a method that enables us to quantify various eicosanoids and 12-HHT using LC-MS/MS analysis. During blood coagulation, 12-HHT levels increased in a time-dependent manner and were relatively higher than those of TxB?, a stable metabolite of TxA?. TxB? production was almost completely inhibited by treatment with ozagrel, an inhibitor of TxA synthase (TxAS), while 12-HHT production was inhibited by 80-90%. Ozagrel-treated blood also exhibited accumulation of PGD? and PGE?, possibly resulting from the shunting of PGH? into synthetic pathways for these prostaglandins. In TxAS-deficient mice, TxB? production during blood coagulation was completely lost, but 12-HHT production was reduced by 80-85%. HEK293 cells transiently expressing TxAS together with cyclooxygenase (COX)-1 or COX-2 produced both TxB? and 12-HHT from arachidonic acid, while HEK293 cells expressing only COX-1 or COX-2 produced significant amounts of 12-HHT but no TxB?. These results clearly demonstrate that 12-HHT is produced by both TxAS-dependent and TxAS-independent pathways in vitro and in vivo.

SUBMITTER: Matsunobu T

PROVIDER: S-EPMC3793602 | biostudies-literature | 2013 Nov

REPOSITORIES: biostudies-literature

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Thromboxane A synthase-independent production of 12-hydroxyheptadecatrienoic acid, a BLT2 ligand.

Matsunobu Takehiko T Okuno Toshiaki T Yokoyama Chieko C Yokomizo Takehiko T

Journal of lipid research 20130905 11

12(S)-hydroxyheptadeca-5Z,8E,10E-trienoic acid (12-HHT) has long been considered a by-product of thromboxane A₂ (TxA₂) biosynthesis with no biological activity. Recently, we reported 12-HHT to be an endogenous ligand for BLT2, a low-affinity leukotriene B4 receptor. To delineate the biosynthetic pathway of 12-HHT, we established a method that enables us to quantify various eicosanoids and 12-HHT using LC-MS/MS analysis. During blood coagulation, 12-HHT levels increased in a time-dependent manner ...[more]

PMID: 24009185

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Project description:BackgroundThromboxane synthase (TxS) metabolizes the cyclooxygenase product, prostaglandin H(2), into thromboxanes. Some of the thromboxanes are known to be biologically active on cancer cells. The aim of the study was to investigate the expression of thromboxane synthases, TBXAS1 and the thromboxane A2 receptor, TBXA2R in a cohort of human breast cancer patients and also to assess their potential clinical relevance.MethodsHuman breast tumour tissues (n = 120) and non-neoplastic mammary tissues (n = 32) were studied. Levels of TBXA2R and TBXAS1 transcripts were quantified using quantitative real-time RT-PCR analysis and correlated with clinical/pathological information including nodal status, grade, prognosis and long term survival (median follow-up period 120 months).ResultsBreast tumour tissue expressed higher levels of TBXA2R compared with normal mammary tissues, although the difference was not statistically significant (p = 0.09). There was no difference between tumour and normal tissues for TBXAS1. However, TBXA2R expression was significantly increased in grade 3 tumours(p = 0.006 vs grade 1), while TBXAS1 was significantly reduced in grade 3 tumours (p = 0.026 vs grade 1 tumours). A similar differential expression pattern was seen in tumours from patients with different prognosis, in that patients with predicted poor prognosis had higher, but not statistically different, levels of TBXA2R, and significantly lower levels of TBXAS1 (p = 0.008). Finally, Kaplan-Meier survival analysis has shown that patients with high levels of TBXA2R had significantly shorter disease free survival (103.8 (79.1-128.5) months) compared with those with low levels (123.7 (112.0-135.3)) months, p = 0.043.ConclusionThromboxane synthases are differentially expressed in human breast cancer. While TBXA2R is highly expressed in aggressive tumours and linked with poor prognosis, TBXAS1 is expressed at significantly low levels in high grade tumours and tumour patients with poor prognosis. TBXA2R thus has a significant prognostic value in clinical breast cancer.

Dataset Information

Thromboxane A synthase-independent production of 12-hydroxyheptadecatrienoic acid, a BLT2 ligand.

Publications

Thromboxane A synthase-independent production of 12-hydroxyheptadecatrienoic acid, a BLT2 ligand.

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