PPARα Genetic Deletion Reveals Global Transcriptional Changes in the Brain and Exacerbates Cerebral Infarction in a Mouse Model of Stroke

TL;DR

This study shows that PPARα protects the brain from stroke by regulating genes involved in inflammation and cell death, suggesting it could be a new drug target.

Contribution

The study reveals PPARα's protective role in stroke through global transcriptional changes and identifies novel gene pathways affected by its deletion.

Findings

PPARα knockout increased brain infarct size, showing its protective role in stroke.

PPARα deletion altered gene expression related to inflammation, apoptosis, and EMT in stroke brains.

Key pathways like TNFα and IL6/STAT3 signaling were upregulated in PPARα knockout stroke brains.

Abstract

Ischemic stroke is a leading cause of death and disability worldwide. Currently, there is an unmet clinical need for pharmacological treatments that can improve ischemic stroke outcomes. In this study, we investigated the role of brain peroxisome proliferator-activated receptor alpha (PPARα) in ischemic stroke pathophysiology. We used a well-established model of cerebral ischemia in PPARα transgenic mice and conducted the RNA sequencing (RNA-seq) of mouse stroke brains harvested 48 h post-middle cerebral artery occlusion (MCAO). PPARα knockout (KO) increased brain infarct size following stroke, indicating a protective role of PPARα in brain ischemia. Our RNA-seq analysis showed that PPARα KO altered the expression of genes in mouse brains with known roles in ischemic stroke pathophysiology. We also identified many other differentially expressed genes (DEGs) upon the loss of PPARα that correlated with increased infarct size in our stroke model. Gene set enrichment analysis (GSEA) and Gene Ontology (GO) analysis revealed the upregulation of gene signatures for the positive regulation of leukocyte proliferation, apoptotic processes, acute-phase response, and cellular component disassembly in mouse stroke brains with PPARα KO. In addition, pathway analysis of our RNA-seq data revealed that TNFα signaling, IL6/STAT3 signaling, and epithelial–mesenchymal transition (EMT) gene signatures were increased in PPARα KO stroke brains. Our study highlights PPARα as an attractive drug target for ischemic stroke due to its transcriptional regulation of inflammation-, apoptosis-, and EMT-related genes in brain tissue following ischemia.

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