Nitric oxide promotes cerebral ischemia/reperfusion injury through upregulating hypoxia-inducible factor1-α-associated inflammation and apoptosis in rats. (31st January 2023)

• Record Type: Journal Article
• Authors: Yang, Nan; Yang, Xueqi; Fang, Yalan; Huang, Yuyou; Shi, Wenjuan; Li, Wei; Ding, Mao; An, Qi; Zhao, Yongmei
• Is Part Of: Neuroscience letters. Volume 795(2022)
• Publication Date: 2023-01-31
• Subjects: Cerebral ischemia/reperfusion -- Hypoxia-inducible factor1-α -- Nitric oxide -- Inflammation -- Middle cerebral artery occlusion; Neurology -- Periodicals; Neurology -- Periodicals; Research -- Periodicals; Neurologie -- Périodiques; Neuroanatomie -- Périodiques; Neuropharmacologie -- Périodiques; Neurophysiologie -- Périodiques; Neurology; Periodicals; Electronic journals; 617.48
• DOI: 10.1016/j.neulet.2022.137034
• Languages: English
• ISSNs: 0304-3940

Abstract

Graphical abstract: Highlights: NO accumulation after cerebral I/R led to HIF-1α upregulation. HIF-1α upregulation activated pro-inflammatory cytokines, causing neuronal apoptotic death. Provide potential target for mitigating cerebral I/R injury. Abstract: Nitric oxide (NO) was one of the key factors to sustain hypoxia-inducible factor-1- α (HIF-1α) activation during hypoxia. However, the mechanism by which NO production promotes upregulation of HIF-1α to cause cerebral ischemia/reperfusion (I/R) injury remains unclear. The present study investigated whether eliminating NO would decrease HIF-1α level, and then reduce the subsequent inflammatory actions as well as neuronal apoptotic death in middle cerebral artery occlusion (MCAO) rats. Our results revealed that HIF-1α was correlated with 3-NT, a marker for nitrosative/oxidative stress, in the brain of MCAO rats. Treatment with NOS inhibitor L-NAME suppressed HIF-1α/3-NT double-positive cells, suggesting that HIF-1α was correlated with NO overproduction during cerebral I/R. Furthermore, pro-inflammatory cytokines TNF-α, IL-1β and NF-κB p65 were significantly increased and colocalized with HIF-1α in the brain of MCAO rats, all of which could be attenuated by NO inhibition, suggesting that eliminating NO reduced MCAO-induced HIF-1α upregulation, which in turn exerted anti-inflammatory actions. Accordingly, cleaved caspase-3, as well as HIF-1α and TUNEL double-positive cells in ischemic brain were also decreased by L-NAME treatment. These results suggest that NO accumulation after cerebral ischemia leads to HIF-1α upregulation, which may activate pro-inflammatory cytokines, resulting in neuronal apoptotic death. These findings demonstrate a novel mechanism of NO-induced cerebral I/R injury.