{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,20]],"date-time":"2026-07-20T10:24:59Z","timestamp":1784543099112,"version":"3.55.0"},"reference-count":58,"publisher":"MDPI AG","issue":"9","license":[{"start":{"date-parts":[[2025,4,25]],"date-time":"2025-04-25T00:00:00Z","timestamp":1745539200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"National Institute of Neurological Disorders and Stroke","award":["7R01NS110370-06"],"award-info":[{"award-number":["7R01NS110370-06"]}]},{"name":"Division of Biomedical Sciences, School of Medicine at the University of California, Riverside","award":["7R01NS110370-06"],"award-info":[{"award-number":["7R01NS110370-06"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>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 (PPAR\u03b1) in ischemic stroke pathophysiology. We used a well-established model of cerebral ischemia in PPAR\u03b1 transgenic mice and conducted the RNA sequencing (RNA-seq) of mouse stroke brains harvested 48 h post-middle cerebral artery occlusion (MCAO). PPAR\u03b1 knockout (KO) increased brain infarct size following stroke, indicating a protective role of PPAR\u03b1 in brain ischemia. Our RNA-seq analysis showed that PPAR\u03b1 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 PPAR\u03b1 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 PPAR\u03b1 KO. In addition, pathway analysis of our RNA-seq data revealed that TNF\u03b1 signaling, IL6\/STAT3 signaling, and epithelial\u2013mesenchymal transition (EMT) gene signatures were increased in PPAR\u03b1 KO stroke brains. Our study highlights PPAR\u03b1 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.<\/jats:p>","DOI":"10.3390\/ijms26094082","type":"journal-article","created":{"date-parts":[[2025,4,25]],"date-time":"2025-04-25T08:02:57Z","timestamp":1745568177000},"page":"4082","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["PPAR\u03b1 Genetic Deletion Reveals Global Transcriptional Changes in the Brain and Exacerbates Cerebral Infarction in a Mouse Model of Stroke"],"prefix":"10.3390","volume":"26","author":[{"given":"Milton H.","family":"Hamblin","sequence":"first","affiliation":[{"name":"Division of Biomedical Sciences, School of Medicine, University of California Riverside, Riverside, CA 92521, USA"},{"name":"Health Sciences Center, Tulane University, New Orleans, LA 70112, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Austin C.","family":"Boese","sequence":"additional","affiliation":[{"name":"School of Medicine, Emory University, Atlanta, GA 30322, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0004-5297-8307","authenticated-orcid":false,"given":"Rabi","family":"Murad","sequence":"additional","affiliation":[{"name":"Bioinformatics, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA 92037, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jean-Pyo","family":"Lee","sequence":"additional","affiliation":[{"name":"Division of Biomedical Sciences, School of Medicine, University of California Riverside, Riverside, CA 92521, USA"},{"name":"Department of Physiology, Tulane University School of Medicine, New Orleans, LA 70112, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,4,25]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"e347","DOI":"10.1161\/CIR.0000000000001209","article-title":"2024 Heart Disease and Stroke Statistics: A Report of US and Global Data from the American Heart Association","volume":"149","author":"Martin","year":"2024","journal-title":"Circulation"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1849","DOI":"10.1161\/STROKEAHA.108.534503","article-title":"Temporal and spatial dynamics of cerebral immune cell accumulation in stroke","volume":"40","author":"Gelderblom","year":"2009","journal-title":"Stroke"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"408","DOI":"10.1016\/j.freeradbiomed.2007.04.020","article-title":"Role of Nrf2 in protection against intracerebral hemorrhage injury in mice","volume":"43","author":"Wang","year":"2007","journal-title":"Free Radic. 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