2. Academic Validation
  3. GIV/Girdin Modulation of Microglial Activation in Ischemic Stroke: Impact of FTO-Mediated m6A Modification

GIV/Girdin Modulation of Microglial Activation in Ischemic Stroke: Impact of FTO-Mediated m6A Modification

  • Mol Neurobiol. 2024 Nov 19. doi: 10.1007/s12035-024-04604-8.
Peng Xie # 1 2,  Mingyan Xia # 3 4,  Tingting Long 4,  Dongfen Guo 3 4,  Wenpeng Cao 4,  Ping Sun 5,  Wenfeng Yu 6 7 8
Affiliations

Affiliations

  • 1 Key Laboratory of Molecular Biology, School of Basic Medical Sciences, Guizhou Medical University, Guiyang, Guizhou, China. 1911839928@qq.com.
  • 2 Department of Human AnatomySchool of Basic Medical ScienceGuian New District, Guizhou Medical University, Guiyang, Guizhou, China. 1911839928@qq.com.
  • 3 Key Laboratory of Molecular Biology, School of Basic Medical Sciences, Guizhou Medical University, Guiyang, Guizhou, China.
  • 4 Department of Human AnatomySchool of Basic Medical ScienceGuian New District, Guizhou Medical University, Guiyang, Guizhou, China.
  • 5 Department of Neurology, The Second People's Hospital of Guiyang, Guiyang, Guiyang, China.
  • 6 Key Laboratory of Molecular Biology, School of Basic Medical Sciences, Guizhou Medical University, Guiyang, Guizhou, China. wenfengyu@gmc.edu.cn.
  • 7 Department of Human AnatomySchool of Basic Medical ScienceGuian New District, Guizhou Medical University, Guiyang, Guizhou, China. wenfengyu@gmc.edu.cn.
  • 8 Key Laboratory of Human Brain Bank for Functions and Diseases of Department of Education of Guizhou Province, Guizhou Medical University, Guiyang, Guizhou, China. wenfengyu@gmc.edu.cn.
  • # Contributed equally.
PMID: 39560901 DOI: 10.1007/s12035-024-04604-8
Abstract

Ischemic stroke (IS) is one of the most common causes of death in the world. The lack of effective pharmacological treatments for IS was primarily due to a lack of understanding of its pathogenesis. Gα-Interacting vesicle-associated protein (GIV/Girdin) is a multi-modular signal transducer and guanine nucleotide exchange factor that controls important signaling downstream of multiple receptors. The purpose of this study was to investigate the role of GIV in IS. In the present study, we found that GIV is highly expressed in the central nervous system (CNS). GIV protein level was decreased, while GIV transcript level was increased in the middle cerebral artery occlusion reperfusion (MCAO/R) mice model. Additionally, GIV was insensitive lipopolysaccharide (LPS) exposure. Interestingly, we found that GIV overexpression dramatically restrained microglial activation, inflammatory response, and M1 polarization in BV-2 microglia induced by oxygen-glucose deprivation and reoxygenation (OGD/R). On the contrary, GIV knockdown had the opposite impact. Mechanistically, we found that GIV activated the Wnt/β-catenin signaling pathway by interacting with DVL2 (disheveled segment polarity protein 2). Notably, m6A demethylase fat mass and obesity-associated protein (FTO) decreased the N6-methyladenosine (m6A) modification-mediated increase of GIV expression and attenuated the inflammatory response in BV-2 stimulated by OGD/R. Taken together, our results demonstrate that GIV inhibited the inflammatory response via activating the Wnt/β-catenin signaling pathway which expression regulated in an FTO-mediated m6A modification in IS. These results broaden our understanding of the role of the FTO-GIV axis in IS development.

Keywords

FTO; GIV/Girdin; Inflammatory response; Ischemic stroke; M6A.

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