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Summary
Our own study as well as others have previously reported that hypoxia activates 15-lipoxygenase (15-LO) in the brain, causing a series of chain reactions, which exacerbates ischemic stroke. 15-hydroxyeicosatetraenoic acid (15-HETE) and 15-oxoeicosatetraenoic acid (15-oxo-ETE/15-KETE) are 15-LO-specific metabolites of arachidonic acid (AA). 15-HETE was found to be rapidly converted into 15-oxo-ETE by 15-hydroxyprostaglandin dehydrogenase (15-PGDH) in some circumstances. We have demonstrated that 15-HETE promotes cerebral vasoconstriction during hypoxia. However, the effect of 15-oxo-ETE upon the contraction of cerebral vasculature remains unclear. To investigate this effect and to clarify the underlying mechanism, we performed immunohistochemistry and Western blot to test the expression of 15-PGDH in rat cerebral tissue, examined internal carotid artery (ICA) tension in isolated rat ICA rings. Western blot and reverse transcription polymerase chain reaction (RT-PCR) were used to analyze the expression of voltage-gated potassium (Kv) channels (Kv2.1, Kv1.5, and Kv1.1) in cultured cerebral arterial smooth muscle cells (CASMCs). The results showed that the levels of 15-PGDH expression were drastically elevated in the cerebral of rats with hypoxia, and 15-oxo-ETE enhanced ICA contraction in a dose-dependent manner. This effect was more significant in the hypoxic rats than in the normoxic rats. We also found that 15-oxo-ETE significantly attenuated the expression of Kv2.1 and Kv1.5, but not Kv1.1. In conclusion, these results suggest that 15-oxo-ETE leads to the contraction of the ICA, especially under hypoxic conditions and that specific Kv channels may play an important role in 15-oxo-ETE-induced ICA constriction.
Key words
15-oxo-eicosatetraenoic acid * 15-lipoxygenase * Voltage-gated potassium channels * Hypoxia * Cerebral vasoconstriction
Introduction
5-oxo-eicosatetraenoic acid (15-oxo-ETE/ 15-KETE) was originally shown to arise from 15-PGDHmediated oxidation of 15-hydroxyeicosatetraenoic acid (15-HETE) in rabbit lung (Bergholte et al. 1987). 15-hydroxyprostaglandin dehydrogenase (15-PGDH) catalyzes the oxidation of 15(S)-hydroxyl group of prostaglandins and lipoxins, which has been considered the key enzyme responsible for the biological inactivation of these eicosanoids (Ensor and Tai 1995). 15-oxo-ETE was also observed as an arachidonic acid (AA) metabolite formed in human mast cells (Gulliksson et al. 2007). Previous studies have shown that the expression of 15-lipoxygenase (15-LO) in the internal carotid artery (ICA) was increased during hypoxia (Zhu et al. 2010). 15-LO catalyzes AA into 15-HETE and 15-oxo-ETE. 15-HETE was also found to be rapidly converted into 15-oxo-ETE (Guo...