{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,30]],"date-time":"2025-10-30T14:45:30Z","timestamp":1761835530611,"version":"build-2065373602"},"reference-count":35,"publisher":"Portland Press Ltd.","issue":"10","license":[{"start":{"date-parts":[[2025,9,26]],"date-time":"2025-09-26T00:00:00Z","timestamp":1758844800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["portlandpress.com"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2025,10,30]]},"abstract":"<jats:p>FGR proto-oncogene (Fgr), a member of the Src family kinases, has garnered attention for its potential involvement in apoptotic signaling, yet its role in cardiovascular diseases, particularly acute myocardial infarction (AMI), remains unexplored. This study sought to investigate whether elevated left ventricular Fgr expression alleviates myocardial injury in the infarcted area and whether this protective mechanism is mediated by modulating phosphoinositide 3-kinase (PI3K)\/Akt phosphorylation. The transcriptome-wide association study was initially utilized to screen for susceptibility genes in the left ventricle, with findings validated using bulk-RNA sequencing data from a rat model of left anterior descending coronary artery (LAD) ligation; subsequently, human spatial transcriptomics combined with single-nucleus RNA sequencing data confirmed differential expression of Fgr and PI3K\/Akt in the infarcted region. Fgr knockdown via siRNA in H9C2 cells and pharmacological inhibition with TL02-59 in rats were conducted to assess cellular survival and cardiac function, respectively. Fgr emerged as a common candidate gene identified through multi-omics data analysis, with its up-regulation confirmed both in vivo and in vitro. Fgr silencing in an in vitro oxygenglucose deprivation model significantly reduced cell survival and suppressed PI3K\/Akt phosphorylation, whereas TL02-59 administration in rats subjected to LAD ligation impaired post-infarction cardiac function while concurrently inhibiting PI3K\/Akt phosphorylation levels. This study demonstrates that Fgr is markedly up-regulated in AMI and exerts cardioprotective effects, possibly through modulation of PI3K\/Akt signaling phosphorylation, thereby underscoring its potential as a therapeutic target.<\/jats:p>","DOI":"10.1042\/bsr20253737","type":"journal-article","created":{"date-parts":[[2025,9,26]],"date-time":"2025-09-26T15:30:52Z","timestamp":1758900652000},"page":"615-633","update-policy":"https:\/\/doi.org\/10.1042\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["High expression of Fgr in the left ventricle attenuates myocardial injury in the infarcted region via regulating the phosphorylation level of PI3K\/Akt"],"prefix":"10.1042","volume":"45","author":[{"ORCID":"https:\/\/orcid.org\/0009-0001-7216-9353","authenticated-orcid":false,"given":"Dongpu","family":"Shao","sequence":"first","affiliation":[{"name":"Department of Cardiology, First Hospital of Jilin University, Changchun, Jilin, 130021, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4501-6423","authenticated-orcid":false,"given":"Zhiguo","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Cardiology, First Hospital of Jilin University, Changchun, Jilin, 130021, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0009-9053-5220","authenticated-orcid":false,"given":"Honglei","family":"Ji","sequence":"additional","affiliation":[{"name":"Department of Cardiology, First Hospital of Jilin University, Changchun, Jilin, 130021, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0005-9862-9580","authenticated-orcid":false,"given":"Lei","family":"Shi","sequence":"additional","affiliation":[{"name":"Department of Cardiology, First Hospital of Jilin University, Changchun, Jilin, 130021, China"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"288","published-online":{"date-parts":[[2025,10,13]]},"reference":[{"key":"2025103010422546800_BSR-2025-3737C1","doi-asserted-by":"crossref","first-page":"2350","DOI":"10.1016\/j.jacc.2023.11.007","article-title":"Global burden of cardiovascular diseases and risks, 1990-2022","volume":"82","author":"Mensah","year":"2023","journal-title":"J. Am. Coll. Cardiol"},{"key":"2025103010422546800_BSR-2025-3737C2","doi-asserted-by":"crossref","first-page":"3720","DOI":"10.1093\/eurheartj\/ehad191","article-title":"ESC Guidelines for the management of acute coronary syndromes: Developed by the task force on the management of acute coronary syndromes of the European Society of Cardiology (ESC)","volume":"44","author":"Byrne","year":"2023","journal-title":"Eur. Heart J."},{"key":"2025103010422546800_BSR-2025-3737C3","doi-asserted-by":"crossref","first-page":"795","DOI":"10.1016\/S0140-6736(19)32008-2","article-title":"Modifiable risk factors, cardiovascular disease, and mortality in 155\u2008722 individuals from 21 high-income, middle-income, and low-income countries (PURE): a prospective cohort study","volume":"395","author":"Yusuf","year":"2020","journal-title":"The Lancet"},{"key":"2025103010422546800_BSR-2025-3737C4","doi-asserted-by":"crossref","first-page":"237","DOI":"10.1093\/eurheartj\/ehy462","article-title":"Fourth universal definition of myocardial infarction (2018)","volume":"40","author":"Thygesen","year":"2019","journal-title":"Eur. Heart J."},{"key":"2025103010422546800_BSR-2025-3737C5","doi-asserted-by":"crossref","first-page":"16","DOI":"10.1016\/j.ancard.2022.11.001","article-title":"Impact de la pr\u00e9sentation extrahospitali\u00e8re en zone recul\u00e9e des patients ayant un infarctus du myocarde avec sus-d\u00e9calage du segment ST: du r\u00e9seau Nord-Alpin des Urgences [RENAU]","volume":"72","author":"Caullery","year":"2023","journal-title":"Annales de Cardiologie et d\u2019Ang\u00e9iologie"},{"key":"2025103010422546800_BSR-2025-3737C6","doi-asserted-by":"crossref","first-page":"773","DOI":"10.1038\/s41569-020-0403-y","article-title":"Myocardial ischaemia-reperfusion injury and cardioprotection in perspective","volume":"17","author":"Heusch","year":"2020","journal-title":"Nat. Rev. Cardiol."},{"key":"2025103010422546800_BSR-2025-3737C7","article-title":"Signaling pathways and targeted therapy for myocardial infarction","volume":"7","author":"Zhang","year":"2022","journal-title":"Signal Transduct. Target. Ther."},{"key":"2025103010422546800_BSR-2025-3737C8","doi-asserted-by":"crossref","first-page":"282","DOI":"10.1161\/CIRCRESAHA.117.310183","article-title":"PI3K and calcium signaling in cardiovascular disease","volume":"121","author":"Ghigo","year":"2017","journal-title":"Circ. Res."},{"key":"2025103010422546800_BSR-2025-3737C9","doi-asserted-by":"crossref","first-page":"966","DOI":"10.1016\/j.celrep.2019.06.065","article-title":"PDGFR-\u03b2 Signaling Regulates Cardiomyocyte Proliferation and Myocardial Regeneration","volume":"28","author":"Yue","year":"2019","journal-title":"Cell Rep"},{"key":"2025103010422546800_BSR-2025-3737C10","doi-asserted-by":"crossref","first-page":"218","DOI":"10.1016\/j.ejphar.2016.06.032","article-title":"GHSR-1a is a novel pro-angiogenic and anti-remodeling target in rats after myocardial infarction","volume":"788","author":"Yuan","year":"2016","journal-title":"Eur. J. Pharmacol"},{"key":"2025103010422546800_BSR-2025-3737C11","doi-asserted-by":"crossref","first-page":"489","DOI":"10.1161\/CIRCRESAHA.117.311147","article-title":"New Insights Into the Role of mTOR Signaling in the Cardiovascular System","volume":"122","author":"Sciarretta","year":"2018","journal-title":"Circ. Res."},{"key":"2025103010422546800_BSR-2025-3737C12","doi-asserted-by":"crossref","first-page":"147","DOI":"10.1016\/j.pharmthera.2004.11.006","article-title":"Modulation of apoptosis by nitric oxide: implications in myocardial ischemia and heart failure","volume":"106","author":"Razavi","year":"2005","journal-title":"Pharmacol. Ther."},{"key":"2025103010422546800_BSR-2025-3737C13","article-title":"The FoxO family in cardiac function and dysfunction","author":"Sarah","year":"2010","journal-title":"Annu. Rev. Physiol."},{"key":"2025103010422546800_BSR-2025-3737C14","doi-asserted-by":"crossref","first-page":"414","DOI":"10.14348\/molcells.2023.0060","article-title":"Disulfidptosis: disulfide stress mediates a novel cell death pathway via actin cytoskeletal vulnerability","volume":"46","author":"Shao","year":"2023","journal-title":"Mol. Cells"},{"key":"2025103010422546800_BSR-2025-3737C15","doi-asserted-by":"crossref","first-page":"988","DOI":"10.1038\/nrd1902","article-title":"Exploiting the PI3K\/AKT pathway for cancer drug discovery","volume":"4","author":"Hennessy","year":"2005","journal-title":"Nat. Rev. Drug Discov."},{"key":"2025103010422546800_BSR-2025-3737C16","doi-asserted-by":"crossref","DOI":"10.1186\/s13045-021-01137-8","article-title":"Targeting Akt in cancer for precision therapy","volume":"14","author":"Hua","year":"2021","journal-title":"J. Hematol. Oncol."},{"key":"2025103010422546800_BSR-2025-3737C17","doi-asserted-by":"crossref","first-page":"29","DOI":"10.1111\/j.1755-5922.2010.00206.x","article-title":"PI3K inhibitors in cardiovascular disease","volume":"29","author":"Eisenreich","year":"2011","journal-title":"Cardiovasc. Ther."},{"key":"2025103010422546800_BSR-2025-3737C18","doi-asserted-by":"crossref","first-page":"110121","DOI":"10.1016\/j.biopha.2020.110121","article-title":"Nicorandil reversed homocysteine-induced coronary microvascular dysfunction via regulating PI3K\/Akt\/eNOS pathway","volume":"127","author":"Zhan","year":"2020","journal-title":"Biomedicine & Pharmacotherapy"},{"key":"2025103010422546800_BSR-2025-3737C19","doi-asserted-by":"crossref","first-page":"740","DOI":"10.1038\/s41588-020-0631-4","article-title":"Mendelian randomization accounting for correlated and uncorrelated pleiotropic effects using genome-wide summary statistics","volume":"52","author":"Morrison","year":"2020","journal-title":"Nat. Genet."},{"key":"2025103010422546800_BSR-2025-3737C20","article-title":"Spatiotemporal transcriptome analysis reveals critical roles for mechano-sensing genes at the border zone in remodeling after myocardial infarction","author":"Shintaro","year":"2022","journal-title":"Nat Cardiovasc Res"},{"key":"2025103010422546800_BSR-2025-3737C21","doi-asserted-by":"crossref","first-page":"766","DOI":"10.1038\/s41586-022-05060-x","article-title":"Spatial multi-omic map of human myocardial infarction","volume":"608","author":"Kuppe","year":"2022","journal-title":"Nature"},{"key":"2025103010422546800_BSR-2025-3737C22","doi-asserted-by":"crossref","first-page":"919","DOI":"10.1093\/eurheartj\/ehaa1040","article-title":"Genome-wide analysis identifies novel susceptibility loci for myocardial infarction","volume":"42","author":"Hartiala","year":"2021","journal-title":"Eur. Heart J."},{"key":"2025103010422546800_BSR-2025-3737C23","doi-asserted-by":"crossref","first-page":"245","DOI":"10.1038\/ng.3506","article-title":"Integrative approaches for large-scale transcriptome-wide association studies","volume":"48","author":"Gusev","year":"2016","journal-title":"Nat. Genet."},{"key":"2025103010422546800_BSR-2025-3737C24","doi-asserted-by":"crossref","first-page":"580","DOI":"10.1038\/ng.2653","article-title":"The genotype-tissue expression (GTEx) project","volume":"45","author":"Lonsdale","year":"2013","journal-title":"Nat. Genet."},{"key":"2025103010422546800_BSR-2025-3737C25","doi-asserted-by":"crossref","first-page":"481","DOI":"10.1038\/ng.3538","article-title":"Integration of summary data from GWAS and eQTL studies predicts complex trait gene targets","volume":"48","author":"Zhu","year":"2016","journal-title":"Nat. Genet."},{"key":"2025103010422546800_BSR-2025-3737C26","doi-asserted-by":"crossref","DOI":"10.1371\/journal.pgen.1004383","article-title":"Bayesian test for colocalisation between pairs of genetic association studies using summary statistics","volume":"10","author":"Giambartolomei","year":"2014","journal-title":"PLOS Genet."},{"key":"2025103010422546800_BSR-2025-3737C27","doi-asserted-by":"crossref","DOI":"10.1038\/s41467-021-26280-1","article-title":"Finding genetically-supported drug targets for Parkinson\u2019s disease using Mendelian randomization of the druggable genome","volume":"12","author":"Storm","year":"2021","journal-title":"Nat. Commun."},{"key":"2025103010422546800_BSR-2025-3737C28","doi-asserted-by":"crossref","first-page":"1551","DOI":"10.1021\/acschembio.8b00154","article-title":"Selective inhibition of the myeloid src-family kinase fgr potently suppresses aml cell growth in Vitro and in Vivo","volume":"13","author":"Weir","year":"2018","journal-title":"ACS Chem. Biol."},{"key":"2025103010422546800_BSR-2025-3737C29","article-title":"An Fgr kinase inhibitor attenuates sepsis-associated encephalopathy by ameliorating mitochondrial dysfunction, oxidative stress, and neuroinflammation via the SIRT1\/PGC-1\u03b1 signaling pathway","volume":"21","author":"Liu","year":"2023","journal-title":"J. Transl. Med."},{"key":"2025103010422546800_BSR-2025-3737C30","doi-asserted-by":"crossref","first-page":"2020","DOI":"10.1002\/1878-0261.13625","article-title":"Kinase activities in pancreatic ductal adenocarcinoma with prognostic and therapeutic avenues","volume":"18","author":"Vall\u00e9s-Mart\u00ed","year":"2024","journal-title":"Mol. Oncol"},{"key":"2025103010422546800_BSR-2025-3737C31","doi-asserted-by":"crossref","first-page":"7760","DOI":"10.1111\/febs.16197","article-title":"Src family kinases (SFKs): critical regulators of microglial homeostatic functions and neurodegeneration in Parkinson\u2019s and Alzheimer\u2019s diseases","volume":"289","author":"Portugal","year":"2022","journal-title":"FEBS J."},{"key":"2025103010422546800_BSR-2025-3737C32","doi-asserted-by":"crossref","DOI":"10.3389\/fcell.2022.1078180","article-title":"Apoptosis regulation by the tyrosine-protein kinase CSK","volume":"10","author":"Fortner","year":"2022","journal-title":"Front. Cell Dev. Biol."},{"key":"2025103010422546800_BSR-2025-3737C33","doi-asserted-by":"crossref","DOI":"10.1038\/s41419-021-03596-w","article-title":"The fatty acid receptor CD36 promotes HCC progression through activating Src\/PI3K\/AKT axis-dependent aerobic glycolysis","volume":"12","author":"Luo","year":"2021","journal-title":"Cell Death Dis."},{"key":"2025103010422546800_BSR-2025-3737C34","first-page":"3219","article-title":"JAK3\/STAT3 oncogenic pathway and PRDM1 expression stratify clinicopathologic features of extranodal NK\/T\u2011cell lymphoma, nasal type","volume":"41","author":"Liu","year":"2019","journal-title":"Oncol. Rep."},{"key":"2025103010422546800_BSR-2025-3737C35","doi-asserted-by":"crossref","first-page":"490","DOI":"10.1161\/CIRCULATIONAHA.114.012316","article-title":"Hck\/Fgr Kinase deficiency reduces plaque growth and stability by blunting monocyte recruitment and intraplaque motility","volume":"132","author":"Medina","year":"2015","journal-title":"Circulation"}],"container-title":["Bioscience Reports"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/portlandpress.com\/bioscirep\/article-pdf\/45\/10\/615\/978567\/bsr-2025-3737.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/portlandpress.com\/bioscirep\/article-pdf\/45\/10\/615\/978567\/bsr-2025-3737.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,30]],"date-time":"2025-10-30T14:42:36Z","timestamp":1761835356000},"score":1,"resource":{"primary":{"URL":"https:\/\/portlandpress.com\/bioscirep\/article\/45\/10\/615\/236580\/High-expression-of-Fgr-in-the-left-ventricle"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,10]]},"references-count":35,"journal-issue":{"issue":"10","published-print":{"date-parts":[[2025,10,30]]}},"URL":"https:\/\/doi.org\/10.1042\/bsr20253737","relation":{},"ISSN":["0144-8463","1573-4935"],"issn-type":[{"type":"print","value":"0144-8463"},{"type":"electronic","value":"1573-4935"}],"subject":[],"published-other":{"date-parts":[[2025,10]]},"published":{"date-parts":[[2025,10]]}}}