Thrombosis or embolism causes blood flow stoppage, resulting in ischemic stroke (IS), the most frequent clinical cerebrovascular disorder. It accounts for more than 80% of all strokes and has a significant disability and mortality rate. Regulating critical targets to stop the ischemia pathophysiological cascade and preserve brain cells is essential for treating IS. We included a deCODE analysis encompassing data on cis-acting variations for 4719 blood proteins. The IS summary statistics consist of 11,929 cases and 472,192 controls. We identified blood proteins associated with IS susceptibility using the Mendelian randomization (MR) method. We comprehensively analyzed the GSE58294 dataset, including differential expression gene identification, functional enrichment analysis, weighted gene co-expression network analysis, least absolute shrinkage and selection operator analysis, and transcription factor identification. The expression patterns of key genes were identified using single-cell sequencing data. The oxygen-glucose deprivation/reperfusion (OGD/R) model was established, and myocyte enhancer factor 2 A (MEF2A) was overexpressed in Neuro-2a/PC12 cells using an overexpression vector. We used CCK-8 and western blotting to observe the cell viability, oxidative stress level, and p-PI3K and p-Akt protein expression. We discovered 73 blood proteins related to IS, and the sensitivity analysis findings supported the causal associations. The MR results and bioinformatics underwent a thorough examination, revealing MEF2A as a transcription factor involved in the development of IS. Single-cell sequencing results revealed that MEF2A was mostly expressed in microglia and endothelial cells. Additional in vitro experiments showed that overexpression of MEF2A could significantly mitigate OGD/R-induced Neuro-2a/PC12 cell injury and oxidative stress, potentially associated with increased PI3K/Akt protein production. This study, using MR analysis, transcriptomics, and in vitro experiments, identified the transcription factor MEF2A as a potential target for treatment. This gives preclinical evidence for drug development. Not applicable.
Zhang et al. (Mon,) studied this question.