Changes of hypoxia-inducible factor-1 signaling and the effect of cilostazol in chronic cerebral ischemia

摘要

Research Highlights (1) Hypoxia-inducible factor-1 under hypoxia is a hot topic in the field of neural regeneration research. Under hypoxia and ischemia/reperfusion, heme oxygenase-1 is upregulated by hypoxia-inducible factor-1. The available research mainly focuses on the role of hypoxia-inducible factor-1 and heme oxygenase-1 following acute cerebral ischemia and hypoxia, while very few studies have examined changes in the hypoxia-inducible factor-1/heme oxygenase-1 signaling pathway. (2) This is the first report showing that the hypoxia-inducible factor-1/heme oxygenase-1 signaling pathway is activated and sustained following chronic cerebral ischemia. (3) Hypoxia-inducible factor-1 and heme oxygenase-1 expression was downregulated by cilostazol in rats subjected to chronic cerebral ischemia. Our findings are the first to show that cilostazol protects against apoptosis in the fontal cortex of chronic cerebral ischemic rats. Cilostazol can provide protection against vascular cognitive impairment through its anti-apoptotic effect. Hypoxia-inducible factor-1 and its specific target gene heme oxygenase-1, are involved in acute cerebral ischemia. However, very few studies have examined in detail the changes in the hypoxia-inducible factor-1/heme oxygenase-1 signaling pathway in chronic cerebral ischemia. In this study, a rat model of chronic cerebral ischemia was established by permanent bilateral common carotid artery occlusion, and these rats were treated with intragastric cilostazol (30 mg/kg) for 9 weeks. Morris water maze results showed that cognitive impairment gradually worsened as the cerebral ischemia proceeded. Immunohistochemistry, semi-quantitative PCR and western blot analysis showed that hypoxia-inducible factor-1α and heme oxygenase-1 expression levels increased after chronic cerebral ischemia, with hypoxia-inducible factor-1α expression peaking at 3 weeks and heme oxygenase-1 expression peaking at 6 weeks. These results suggest that the elevated levels of hypoxia-inducible factor-1α may upregulate heme oxygenase-1 expression following chronic cerebral ischemia and that the hypoxia-inducible factor-1/heme oxygenase-1 signaling pathway is involved in the development of cognitive impairment induced by chronic cerebral ischemia. Cilostazol treatment alleviated the cognitive impairment in rats with chronic cerebral ischemia, decreased hypoxia-inducible factor-1α and heme oxygenase-1 expression levels, and reduced apoptosis in the frontal cortex. These findings demonstrate that cilostazol can protect against cognitive impairment induced by chronic cerebral ischemic injury through an anti-apoptotic mechanism.