Li Ruqi, Huang Tianchen, Zhou Jianpo, Liu Xiansheng, Li Gan, Zhang Yueman, Guo Yunlu, Li Fengshi, Li Yan, Liesz Arthur, Li Peiying, Wang Zhenghong, Wan Jieqing
Cerebrovascular Diseases Center, Department of Neurosurgery, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
Department of Anesthesiology, Key Laboratory of the Ministry of Education, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
CNS Neurosci Ther. 2024 Dec;30(12):e70144. doi: 10.1111/cns.70144.
Hyperlipidemia is a common comorbidity of stroke patients, elucidating the mechanism that underlies the exacerbated ischemic brain injury after stroke with hyperlipidemia is emerging as a significant clinical problem due to the growing proportion of hyperlipidemic stroke patients.
Mice were fed a high-fat diet for 12 weeks to induce hyperlipidemia. Transient middle cerebral artery occlusion was induced as a mouse model of ischemic stroke. Emx1 mice were crossed with Mef2c mice to specifically deplete Mef2c in neurons.
We reported that hyperlipidemia significantly aggravated neuronal necroptosis and exacerbated long-term neurological deficits following ischemic stroke in mice. Mechanistically, Cflar, an upstream necroptotic regulator, was alternatively spliced into pro-necroptotic isoform (Cflar) in ischemic neurons of hyperlipidemic mice. Neuronal Mef2c was a transcription factor modulating Cflar splicing and upregulated by hyperlipidemia following stroke. Neuronal specific Mef2c depletion reduced cerebral level of Cflar and cFLIP (translated by Cflar), while mitigated neuron necroptosis and neurological deficits following stroke in hyperlipidemic mice.
Our study highlights the pathogenic role of Cflar splicing mediated by neuronal Mef2c, which aggravates neuron necroptosis following stroke with comorbid hyperlipidemia and proposes Cflar splicing as a potential therapeutic target for hyperlipidemic stroke patients.
高脂血症是中风患者常见的合并症，随着高脂血症中风患者比例的不断增加，阐明高脂血症中风后缺血性脑损伤加重的机制已成为一个重大的临床问题。
给小鼠喂食高脂饮食12周以诱导高脂血症。诱导短暂性大脑中动脉闭塞作为缺血性中风的小鼠模型。将Emx1小鼠与Mef2c小鼠杂交，以特异性耗尽神经元中的Mef2c。
我们报道高脂血症显著加重了小鼠缺血性中风后的神经元坏死性凋亡，并加剧了长期神经功能缺损。机制上，上游坏死性凋亡调节因子Cflar在高脂血症小鼠的缺血神经元中被剪接成促坏死性凋亡异构体（Cflar）。神经元Mef2c是一种调节Cflar剪接的转录因子，在中风后因高脂血症而上调。神经元特异性Mef2c缺失降低了大脑中Cflar和cFLIP（由Cflar翻译）的水平，同时减轻了高脂血症小鼠中风后的神经元坏死性凋亡和神经功能缺损。
我们的研究突出了神经元Mef2c介导的Cflar剪接的致病作用，其加重了合并高脂血症中风后的神经元坏死性凋亡，并提出Cflar剪接作为高脂血症中风患者的潜在治疗靶点。
