Inhibition of 15-lipoxygenase (15-LOX) reverses hypoxia-induced down-regulation of potassium channels Kv1.5 and Kv2.1

The inhibition of voltage-gated potassium channels (Kv) plays an important role in the cerebral hypoxiainduced cell death. The activity of Kv can be inhibited by 15-hydroxyeicosatetrienoic acid (15-HETE). Therefore, as the key enzyme which catalyzed the formation of 15-HETE, 15-LOX may be involved in Kv inhibition induced by cerebral hypoxia. In our study, Wistar rats cerebral arterial smooth muscle cells (CASMCs) were placed under the condition of hypoxia and control, 15-LOX was proved involved in hypoxia-induced vasoconstriction. Furthermore, 15LOX gene over expression under normoxic condition, as well as 15-LOX gene knockout or inhibition under hypoxic condition was performed to investigate the expression and activity of Kv1.5 and Kv2.1 in CASMCs. Results showed that both hypoxia and 15-LOX over expression could cause Kv1.5 and Kv2.1 suppression, but no suppression was observed under hypoxic condition when 15-LOX gene was knockout or inhibited, which made 15-LOX a new target for the treatment of cerebral hypoxia. In conclusion, AA/15-LOX/15-HETE induces vasoconstriction by down-regulating Kv channels, and Kv2.1/1.5 channels are the targets. Our study also suggests a therapeutic strategy to improve ischemic vascular occlusion by lowering 15-HETE level and preventing Kv channel down-regulation, which makes 15-LOX as a new target for the treatment of cerebral hypoxia.