{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,10]],"date-time":"2026-06-10T11:56:34Z","timestamp":1781092594555,"version":"3.54.1"},"reference-count":36,"publisher":"Portland Press Ltd.","issue":"7","license":[{"start":{"date-parts":[[2026,5,28]],"date-time":"2026-05-28T00:00:00Z","timestamp":1779926400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/2.0\/"}],"funder":[{"DOI":"10.13039\/n\/a","name":"The yellow crane of excellence program","doi-asserted-by":"publisher","award":["HHYC2019003"],"award-info":[{"award-number":["HHYC2019003"]}],"id":[{"id":"10.13039\/n\/a","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["portlandpress.com"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2026,7,15]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Signal regulatory protein-\u03b1 (SIRPA) serves as a pivotal immune checkpoint by binding to CD47, a mechanism recognized for its antitumor potential and increasing relevance in cardiovascular diseases. However, the role and regulatory mechanisms of SIRPA in intimal hyperplasia remain poorly defined. GEO databases revealed that SIRPA expression is elevated in human atherosclerotic plaques and in-stent restenosis patients. In current study, we utilized wire-injured mouse carotid arteries and macrophages stimulated with LPS or IL-4 to demonstrate significant upregulation of SIRPA following injury and pro-inflammatory stimulation, as confirmed by RT-PCR and immunoblotting. Double immunofluorescence staining showed predominant SIRPA expression localized to macrophages in the neointima of murine arteries and plaques of human atherosclerotic coronary arteries. Global SIRPA-knockout (SIRPA-KO) mice and bone marrow transplantation from SIRPA-KO to wild-type mice showed that macrophage-specific SIRPA deletion mitigated wire injury-induced intimal hyperplasia. Loss-of-function experiments in bone marrow-derived macrophages indicated that SIRPA depletion reduced classical M1 polarization while enhancing alternative M2 activation. Subsequent coculture assays revealed that the reprogramming of macrophages due to SIRPA ablation suppressed vascular smooth muscle cell (VSMC) proliferation, migration, and dedifferentiation. Furthermore, the protective effect of SIRPA deficiency on intimal hyperplasia was attributed to enhanced alternative macrophage activation and a consequent reduction in VSMC phenotypic switching. Mechanistically, SIRPA-KO promoted alternative macrophage polarization through PPAR\u03b3 upregulation, as evidenced by the reversal of this phenotype upon treatment with the PPAR\u03b3-specific antagonist G3335. Collectively, these findings unveil a previously unrecognized regulatory axis governing intimal hyperplasia and propose SIRPA as a promising therapeutic target for arterial restenosis.<\/jats:p>","DOI":"10.1042\/cs20250499","type":"journal-article","created":{"date-parts":[[2026,5,28]],"date-time":"2026-05-28T16:12:37Z","timestamp":1779984757000},"page":"1285-1301","update-policy":"https:\/\/doi.org\/10.1042\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["SIRPA ablation inhibits intimal hyperplasia by promoting PPAR\u03b3-regulated alternative macrophage polarization"],"prefix":"10.1042","volume":"140","author":[{"given":"Tao","family":"He","sequence":"first","affiliation":[{"name":"1Department of Cardiology, Zhongnan Hospital, Wuhan University, Wuhan 430071, China"},{"name":"2Institute of Myocardial Injury and Repair, Wuhan University, Wuhan 430071, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaoyan","family":"Wu","sequence":"additional","affiliation":[{"name":"1Department of Cardiology, Zhongnan Hospital, Wuhan University, Wuhan 430071, China"},{"name":"2Institute of Myocardial Injury and Repair, Wuhan University, Wuhan 430071, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Quan","family":"Zhang","sequence":"additional","affiliation":[{"name":"3Pediatric Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ruifeng","family":"Tian","sequence":"additional","affiliation":[{"name":"1Department of Cardiology, Zhongnan Hospital, Wuhan University, Wuhan 430071, China"},{"name":"2Institute of Myocardial Injury and Repair, Wuhan University, Wuhan 430071, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhili","family":"Jin","sequence":"additional","affiliation":[{"name":"1Department of Cardiology, Zhongnan Hospital, Wuhan University, Wuhan 430071, China"},{"name":"2Institute of Myocardial Injury and Repair, Wuhan University, Wuhan 430071, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fei-Xiang","family":"Jiang","sequence":"additional","affiliation":[{"name":"1Department of Cardiology, Zhongnan Hospital, Wuhan University, Wuhan 430071, China"},{"name":"2Institute of Myocardial Injury and Repair, Wuhan University, Wuhan 430071, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiangjie","family":"Kong","sequence":"additional","affiliation":[{"name":"1Department of Cardiology, Zhongnan Hospital, Wuhan University, Wuhan 430071, China"},{"name":"2Institute of Myocardial Injury and Repair, Wuhan University, Wuhan 430071, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Li","family":"Peng","sequence":"additional","affiliation":[{"name":"1Department of Cardiology, Zhongnan Hospital, Wuhan University, Wuhan 430071, China"},{"name":"2Institute of Myocardial Injury and Repair, Wuhan University, Wuhan 430071, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ming","family":"Chen","sequence":"additional","affiliation":[{"name":"1Department of Cardiology, Zhongnan Hospital, Wuhan University, Wuhan 430071, China"},{"name":"2Institute of Myocardial Injury and Repair, Wuhan University, Wuhan 430071, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fang","family":"Zhao","sequence":"additional","affiliation":[{"name":"1Department of Cardiology, Zhongnan Hospital, Wuhan University, Wuhan 430071, China"},{"name":"2Institute of Myocardial Injury and Repair, Wuhan University, Wuhan 430071, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hairong","family":"Wang","sequence":"additional","affiliation":[{"name":"1Department of Cardiology, Zhongnan Hospital, Wuhan University, Wuhan 430071, China"},{"name":"2Institute of Myocardial Injury and Repair, Wuhan University, Wuhan 430071, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0008-1591-4581","authenticated-orcid":false,"given":"Wen-Lin","family":"Cheng","sequence":"additional","affiliation":[{"name":"1Department of Cardiology, Zhongnan Hospital, Wuhan University, Wuhan 430071, China"},{"name":"2Institute of Myocardial Injury and Repair, Wuhan University, Wuhan 430071, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"288","published-online":{"date-parts":[[2026,6,10]]},"reference":[{"key":"2026061006561947400_B1","first-page":"e41","article-title":"2025 heart disease and stroke statistics: A report of us and global data from the american heart association","volume":"151","author":"Martin","year":"2025","journal-title":"Circulation"},{"key":"2026061006561947400_B2","doi-asserted-by":"publisher","first-page":"843712","DOI":"10.3389\/fimmu.2022.843712","article-title":"Macrophage subsets and death are responsible for atherosclerotic plaque formation","volume":"13","author":"Li","year":"2022","journal-title":"Front. Immunol."},{"key":"2026061006561947400_B3","doi-asserted-by":"publisher","first-page":"1413","DOI":"10.1161\/ATVBAHA.108.169144","article-title":"Macrophage function and its impact on atherosclerotic lesion composition, progression, and stability: the good, the bad, and the ugly","volume":"28","author":"Dickhout","year":"2008","journal-title":"Arterioscler. Thromb. Vasc. Biol."},{"key":"2026061006561947400_B4","doi-asserted-by":"publisher","first-page":"e103","DOI":"10.4244\/EIJ-D-21-01034","article-title":"Management of in-stent restenosis","volume":"18","author":"Alfonso","year":"2022","journal-title":"Euro Intervention"},{"key":"2026061006561947400_B5","doi-asserted-by":"publisher","first-page":"180","DOI":"10.1186\/s12964-022-00993-2","article-title":"How vascular smooth muscle cell phenotype switching contributes to vascular disease","volume":"20","author":"Cao","year":"2022","journal-title":"Cell Commun. Signal."},{"key":"2026061006561947400_B6","doi-asserted-by":"publisher","first-page":"79","DOI":"10.1016\/j.jvssci.2021.04.001","article-title":"Targeting smooth muscle cell phenotypic switching in vascular disease","volume":"2","author":"Chakraborty","year":"2021","journal-title":"JVS Vasc. Sci."},{"key":"2026061006561947400_B7","doi-asserted-by":"publisher","first-page":"541","DOI":"10.1146\/annurev-physiol-022516-034339","article-title":"Macrophage polarization","volume":"79","author":"Murray","year":"2017","journal-title":"Annu. Rev. Physiol."},{"key":"2026061006561947400_B8","doi-asserted-by":"publisher","first-page":"691","DOI":"10.1038\/s41419-023-06206-z","article-title":"Macrophage polarization and metabolism in atherosclerosis","volume":"14","author":"Hou","year":"2023","journal-title":"Cell Death Dis."},{"key":"2026061006561947400_B9","doi-asserted-by":"publisher","first-page":"220239","DOI":"10.1098\/rsos.220239","article-title":"Macrophage polarization as a potential therapeutic target for atherosclerosis: A dynamic stochastic modelling study","volume":"9","author":"Liu","year":"2022","journal-title":"R Soc Open Sci."},{"key":"2026061006561947400_B10","doi-asserted-by":"publisher","first-page":"e004589","DOI":"10.1136\/jitc-2022-004589","article-title":"CD47\/SIRP\u03b1 axis: bridging innate and adaptive immunity","volume":"10","author":"van Duijn","year":"2022","journal-title":"J. Immunother. Cancer"},{"key":"2026061006561947400_B11","doi-asserted-by":"publisher","first-page":"712","DOI":"10.4049\/jimmunol.2001019","article-title":"Novel SIRPalpha antibodies that induce single-agent phagocytosis of tumor cells while preserving T cells","volume":"206","author":"Andrejeva","year":"2021","journal-title":"J. Immunol."},{"key":"2026061006561947400_B12","doi-asserted-by":"publisher","first-page":"742","DOI":"10.1016\/j.immuni.2020.04.011","article-title":"The CD47\u2013SIRPalpha immune checkpoint","volume":"52","author":"Logtenberg","year":"2020","journal-title":"Immunity"},{"key":"2026061006561947400_B13","doi-asserted-by":"publisher","first-page":"457","DOI":"10.1038\/nri1859","article-title":"The SIRP family of receptors and immune regulation","volume":"6","author":"Barclay","year":"2006","journal-title":"Nat. Rev. Immunol."},{"key":"2026061006561947400_B14","doi-asserted-by":"publisher","first-page":"834","DOI":"10.1111\/j.1471-4159.2012.07818.x","article-title":"SHP(S)-1 deficiency induces robust neuroprotection against experimental stroke by attenuating oxidative stress","volume":"122","author":"Wang","year":"2012","journal-title":"J. Neurochem."},{"key":"2026061006561947400_B15","doi-asserted-by":"publisher","first-page":"96","DOI":"10.1161\/HYPERTENSIONAHA.113.01506","article-title":"Signal regulatory protein-alpha protects against cardiac hypertrophy via the disruption of toll-like receptor 4 signaling","volume":"63","author":"Jiang","year":"2014","journal-title":"Hypertension"},{"key":"2026061006561947400_B16","doi-asserted-by":"publisher","first-page":"2172","DOI":"10.1016\/j.immuni.2023.08.003","article-title":"CD47 ligation repositions the inhibitory receptor SIRPA to suppress integrin activation and phagocytosis","volume":"56","author":"Morrissey","year":"2023","journal-title":"Immunity"},{"key":"2026061006561947400_B17","doi-asserted-by":"publisher","first-page":"3097","DOI":"10.1093\/cvr\/cvab369","article-title":"Loss of myeloid cell-specific SIRPalpha, but not CD47, attenuates inflammation and suppresses atherosclerosis","volume":"118","author":"Singla","year":"2022","journal-title":"Cardiovasc. Res."},{"key":"2026061006561947400_B18","doi-asserted-by":"publisher","first-page":"28240","DOI":"10.31083\/RCM28240","article-title":"Vascular smooth muscle cells: a therapeutic target in atherosclerosis","volume":"26","author":"Zhao","year":"2025","journal-title":"Rev. Cardiovasc. Med."},{"key":"2026061006561947400_B19","doi-asserted-by":"publisher","first-page":"4060","DOI":"10.3390\/cells11244060","article-title":"Vascular smooth muscle cells phenotypic switching in cardiovascular diseases","volume":"11","author":"Tang","year":"2022","journal-title":"Cells"},{"key":"2026061006561947400_B20","doi-asserted-by":"publisher","first-page":"1067","DOI":"10.3748\/wjg.v22.i3.1067","article-title":"Endothelial dysfunction in inflammatory bowel diseases: pathogenesis, assessment and implications","volume":"22","author":"Cibor","year":"2016","journal-title":"World J. Gastroenterol."},{"key":"2026061006561947400_B21","doi-asserted-by":"publisher","first-page":"222","DOI":"10.5830\/CVJA-2011-068","article-title":"Endothelial dysfunction: the early predictor of atherosclerosis","volume":"23","author":"Mudau","year":"2012","journal-title":"Cardiovasc. J. Afr."},{"key":"2026061006561947400_B22","doi-asserted-by":"publisher","first-page":"315","DOI":"10.1161\/CIRCRESAHA.118.313591","article-title":"Immunity and inflammation in atherosclerosis","volume":"124","author":"Wolf","year":"2019","journal-title":"Circ. Res."},{"key":"2026061006561947400_B23","doi-asserted-by":"publisher","first-page":"1185587","DOI":"10.3389\/fimmu.2023.1185587","article-title":"Macrophage polarization states in atherosclerosis","volume":"14","author":"Wu","year":"2023","journal-title":"Front. Immunol."},{"key":"2026061006561947400_B24","first-page":"3928","article-title":"Blockade of the CD47\/SIRPalpha checkpoint axis potentiates the macrophage-mediated antitumor efficacy of tafasitamab","volume":"109","author":"Biedermann","year":"2024","journal-title":"Haematologica"},{"key":"2026061006561947400_B25","doi-asserted-by":"publisher","first-page":"4354786","DOI":"10.1155\/2019\/4354786","article-title":"Vascular macrophages in atherosclerosis","volume":"2019","author":"Xu","year":"2019","journal-title":"J. Immunol. Res."},{"key":"2026061006561947400_B26","doi-asserted-by":"publisher","first-page":"993","DOI":"10.1016\/j.cell.2005.11.026","article-title":"The many faces of PPARgamma","volume":"123","author":"Lehrke","year":"2005","journal-title":"Cell"},{"key":"2026061006561947400_B27","first-page":"4","article-title":"PPARs: The role in glucose and lipid homeostasis, insulin resistance and atherosclerosis","volume":"53","author":"Hrebicek","year":"2004","journal-title":"Cesk. Fysiol."},{"key":"2026061006561947400_B28","doi-asserted-by":"publisher","first-page":"585","DOI":"10.1016\/S1097-2765(00)80209-9","article-title":"PPAR gamma is required for placental, cardiac, and adipose tissue development","volume":"4","author":"Barak","year":"1999","journal-title":"Mol. Cell."},{"key":"2026061006561947400_B29","doi-asserted-by":"publisher","first-page":"82","DOI":"10.1038\/34184","article-title":"PPAR-gamma agonists inhibit production of monocyte inflammatory cytokines","volume":"391","author":"Jiang","year":"1998","journal-title":"Nature"},{"key":"2026061006561947400_B30","doi-asserted-by":"publisher","first-page":"565","DOI":"10.1007\/s11748-015-0576-1","article-title":"PPAR-gamma agonist attenuates inflammation in aortic aneurysm patients","volume":"63","author":"Motoki","year":"2015","journal-title":"Gen. Thorac. Cardiovasc. Surg."},{"key":"2026061006561947400_B31","doi-asserted-by":"publisher","first-page":"484","DOI":"10.1093\/cvr\/cvr238","article-title":"PPARgamma attenuates intimal hyperplasia by inhibiting TLR4-mediated inflammation in vascular smooth muscle cells","volume":"92","author":"Zhang","year":"2011","journal-title":"Cardiovasc. Res."},{"key":"2026061006561947400_B32","doi-asserted-by":"publisher","first-page":"479","DOI":"10.1016\/j.atherosclerosis.2011.06.009","article-title":"PPARgamma in coronary atherosclerosis: in vivo expression pattern and correlations with hyperlipidemic status and statin treatment","volume":"218","author":"Pucci","year":"2011","journal-title":"Atherosclerosis"},{"key":"2026061006561947400_B33","doi-asserted-by":"publisher","first-page":"672150","DOI":"10.3389\/fphar.2021.672150","article-title":"Jujuboside B inhibits neointimal hyperplasia and prevents vascular smooth muscle cell dedifferentiation, proliferation, and migration via activation of AMPK\/PPAR-gamma signaling","volume":"12","author":"Ji","year":"2021","journal-title":"Front. Pharmacol."},{"key":"2026061006561947400_B34","doi-asserted-by":"publisher","first-page":"7576388","DOI":"10.1155\/2022\/7576388","article-title":"Heme oxygenase 1\/peroxisome proliferator-activated receptor gamma pathway protects intimal hyperplasia and mitigates arteriovenous fistula dysfunction by regulating oxidative stress and inflammatory response","volume":"2022","author":"Xie","year":"2022","journal-title":"Cardiovasc. Ther."},{"key":"2026061006561947400_B35","doi-asserted-by":"publisher","first-page":"287","DOI":"10.3109\/10641963.2010.531845","article-title":"PPARs and their effects on the cardiovascular system","volume":"33","author":"Oyekan","year":"2011","journal-title":"Clin. Exp. Hypertens."},{"key":"2026061006561947400_B36","doi-asserted-by":"publisher","first-page":"S26","DOI":"10.1038\/sj.ijo.0802910","article-title":"New targets for PPARgamma in the vessel wall: implications for restenosis","volume":"29","author":"Bruemmer","year":"2005","journal-title":"Int. J. Obes. (Lond.)"}],"container-title":["Clinical Science"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/portlandpress.com\/clinsci\/article-pdf\/140\/7\/1285\/988595\/cs-2025-0499.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/portlandpress.com\/clinsci\/article-pdf\/140\/7\/1285\/988595\/cs-2025-0499.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,6,10]],"date-time":"2026-06-10T10:56:28Z","timestamp":1781088988000},"score":1,"resource":{"primary":{"URL":"https:\/\/portlandpress.com\/clinsci\/article\/140\/7\/1285\/237625\/SIRPA-ablation-inhibits-intimal-hyperplasia-by"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,6,10]]},"references-count":36,"journal-issue":{"issue":"7","published-print":{"date-parts":[[2026,7,15]]}},"URL":"https:\/\/doi.org\/10.1042\/cs20250499","relation":{},"ISSN":["0143-5221","1470-8736"],"issn-type":[{"value":"0143-5221","type":"print"},{"value":"1470-8736","type":"electronic"}],"subject":[],"published-other":{"date-parts":[[2026,7]]},"published":{"date-parts":[[2026,6,10]]}}}