| First Author | Matsunobu T | Year | 2013 |
| Journal | J Lipid Res | Volume | 54 |
| Issue | 11 | Pages | 2979-87 |
| PubMed ID | 24009185 | Mgi Jnum | J:203820 |
| Mgi Id | MGI:5528779 | Doi | 10.1194/jlr.M037754 |
| Citation | Matsunobu T, et al. (2013) Thromboxane A synthase-independent production of 12-hydroxyheptadecatrienoic acid, a BLT2 ligand. J Lipid Res 54(11):2979-87 |
| abstractText | 12(S)-hydroxyheptadeca-5Z,8E,10E-trienoic acid (12-HHT) has long been considered a by-product of thromboxane A(2) (TxA(2)) 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(2), a stable metabolite of TxA(2). TxB(2) 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(2) and PGE(2), possibly resulting from the shunting of PGH(2) into synthetic pathways for these prostaglandins. In TxAS-deficient mice, TxB(2) 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(2) 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(2). These results clearly demonstrate that 12-HHT is produced by both TxAS-dependent and TxAS-independent pathways in vitro and in vivo. |
