Chu Bo, Zhou Yadong, Zhai Heng, Li Lei, Sun Li, Li Yun
a Department of Critical Medicine, Jinan Central Hospital of Shandong University, Jinan, Shandong 250013, People's Republic of China.
b Department of Emergency Medicine, Tai'an Central Hospital, Tai'an, Shandong 271000, People's Republic of China.
Can J Physiol Pharmacol. 2018 Jun;96(6):611-617. doi: 10.1139/cjpp-2017-0586. Epub 2018 Mar 5.
MicroRNA-146a (miR-146a) is reportedly implicated in the pathogenesis of ischemia-reperfusion (I/R) injury; however, its role in cerebral I/R injury is unclear and requires further investigation. In this study, cerebral I/R injury was established in mice via middle cerebral artery occlusion, and the expression of miR-146a was detected in the brain tissue via quantitative real-time PCR. We found that the expression of miR-146a was upregulated. Furthermore, the endogenous miR-146a was antagonized by its specific inhibitor. The results indicated that the inhibition of miR-146a deteriorated I/R-induced neurobehavioral impairment, exaggerated the infarct size, and exacerbated blood-brain barrier leakage. Cerebral I/R injury-induced generation of inflammatory cytokines, tumor necrosis factor (TNF)-α, interleukin (IL)-1β, and IL-6, was further promoted by miR-146a inhibitor. The expression of interleukin-1 receptor associated kinase 1 (IRAK1), a target of miR-146a, was upregulated upon miR-146a inhibition. In addition, the nuclear factor κB (NF-κB) signaling pathway was over-activated when miR-146a was antagonized as manifested by the increased levels of phospho-NF-κB inhibitor α and nuclear p65. In summary, our findings demonstrate that the elevation of miR-146a may be one of the compensatory responses after the cerebral I/R injury and suggest miR-146a as a potential therapeutic target for cerebral I/R injury.
据报道，微小RNA-146a（miR-146a）与缺血再灌注（I/R）损伤的发病机制有关；然而，其在脑缺血再灌注损伤中的作用尚不清楚，需要进一步研究。在本研究中，通过大脑中动脉闭塞在小鼠中建立脑缺血再灌注损伤模型，并通过定量实时PCR检测脑组织中miR-146a的表达。我们发现miR-146a的表达上调。此外，内源性miR-146a被其特异性抑制剂拮抗。结果表明，抑制miR-146a会使I/R诱导的神经行为损伤恶化，扩大梗死面积，并加剧血脑屏障渗漏。miR-146a抑制剂进一步促进了脑缺血再灌注损伤诱导的炎性细胞因子肿瘤坏死因子（TNF）-α、白细胞介素（IL）-1β和IL-6的产生。miR-146a的靶标白细胞介素-1受体相关激酶1（IRAK1）的表达在miR-146a受到抑制时上调。此外，当miR-146a被拮抗时，核因子κB（NF-κB）信号通路过度激活，表现为磷酸化NF-κB抑制剂α和核p65水平升高。总之，我们的研究结果表明，miR-146a的升高可能是脑缺血再灌注损伤后的代偿反应之一，并提示miR-146a作为脑缺血再灌注损伤的潜在治疗靶点。
