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

Year: 2024

Type: article

Abstract: Ischemic stroke is one of the most common causes of death in the world. The lack of effective pharmacological treatments for ischemic stroke is primarily due to a lack of understanding of its pathogenesis. Gα-Interacting vesicle-associated protein (GIV) is a multimodular 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 ischemic stroke. In the present study, we found that GIV is highly expressed in the central nervous system (CNS). However, GIV protein levels decreased, while GIV transcript level was increased in the middle cerebral artery occlusion (MCAO) model. Additionally, GIV was insensitive LPS exposure. Additionally, we found that GIV overexpression dramatically restrained microglial activation, inflammatory response and M1 polarization in BV2 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. Notably, FTO decreased the m6A modification-mediated increase of GIV expression and attenuated the inflammatory response in BV2 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.

Source: Molecular Neurobiology

DOI: 10.1007/s12035-024-04604-8