Mef2c Exacerbates Neuron Necroptosis via Modulating Alternative Splicing of Cflar in Ischemic Stroke With Hyperlipidemia

Li, Ruqi ; Huang, Tianchen; Zhou, Jianpo; Liu, Xiansheng; Li, Gan; Zhang, Yueman; Guo, Yunlu ; Li, Fengshi; Li, Yan; Liesz, Arthur ; Li, Peiying ; Wang, Zhenghong und Wan, Jieqing (2024): Mef2c Exacerbates Neuron Necroptosis via Modulating Alternative Splicing of Cflar in Ischemic Stroke With Hyperlipidemia. In: CNS Neuroscience & Therapeutics, Bd. 30, Nr. 12, e70144

Abstract

Aim

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.

Methods

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. Emx1Cre mice were crossed with Mef2cfl/fl mice to specifically deplete Mef2c in neurons.

Results

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 (CflarR) 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 CflarR and cFLIPR (translated by CflarR), while mitigated neuron necroptosis and neurological deficits following stroke in hyperlipidemic mice.

Conclusions

Our study highlights the pathogenic role of CflarR splicing mediated by neuronal Mef2c, which aggravates neuron necroptosis following stroke with comorbid hyperlipidemia and proposes CflarR splicing as a potential therapeutic target for hyperlipidemic stroke patients.

• Dokumententyp: Zeitschriftenartikel
• Fakultät: Medizin > Munich Cluster for Systems Neurology (SyNergy)
• Themengebiete: 600 Technik, Medizin, angewandte Wissenschaften > 610 Medizin und Gesundheit
• ISSN: 1755-5930
• Sprache: Englisch
• DFG: Gefördert durch die Deutsche Forschungsgemeinschaft (DFG) - 390857198