{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,22]],"date-time":"2026-09-22T15:48:44Z","timestamp":1790092124183,"version":"4.0.1"},"reference-count":60,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"7","content-domain":{"domain":["www.ahajournals.org"],"crossmark-restriction":true},"short-container-title":["Circulation Research"],"published-print":{"date-parts":[[2025,3,28]]},"abstract":"<jats:sec>\n            <jats:title>BACKGROUND:<\/jats:title>\n            <jats:p>Vascular hyperpermeability is one of the hallmarks of acute lung injury, contributing to excessive inflammation and respiratory failure. The PPAR\u03b4 (peroxisome proliferator-activated receptor delta) is an anti-inflammatory transcription factor, although its role in endothelial barrier function remains unclear. Here, we studied the essential role of PPAR\u03b4 in maintaining vascular endothelial barrier integrity during lung inflammation and investigated the underlying mechanisms.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>METHODS:<\/jats:title>\n            <jats:p>\n              Endothelial cell (EC)\u2013selective PPAR\u03b4 knockout mice (Ppard\n              <jats:sup>EC-KO<\/jats:sup>\n              ) and littermate control mice (Ppard\n              <jats:sup>EC-WT<\/jats:sup>\n              ) received lipopolysaccharide injection to induce acute lung injury. Lung inflammation, pulmonary vascular leakage, and mouse mortality were monitored. Single-cell RNA sequencing was performed on sorted mouse lung ECs.\n            <\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>RESULTS:<\/jats:title>\n            <jats:p>\n              Ppard\n              <jats:sup>EC-KO<\/jats:sup>\n              mice exhibited aggravated lung inflammation, characterized by increased leukocyte infiltration, elevated production of proinflammatory cytokines, and higher mortality rates. The enhanced inflammatory responses were associated with increased protein leakage, interstitial edema, and impaired endothelial barrier structure, leading to vascular hyperpermeability in Ppard\n              <jats:sup>EC-KO<\/jats:sup>\n              mice. Mechanistically, with single-cell RNA sequencing, we identified the emergence of an interferon-activated capillary EC population marked by CXCL10 (C-X-C motif chemokine 10) expression following lipopolysaccharide challenge. PPAR\u03b4 silencing significantly increased CXCL10 expression in ECs through activating STAT1 (Signal transducer and activator of transcription 1). Notably, CXCL10 treatment induced degradation of tight junction proteins ZO-1 (zonula occludens protein 1) and claudin-5 through the ubiquitin-proteasome system, disrupting membrane junction continuity in ECs. Administration of anti-CXCL10 antibody or CXCL10 receptor antagonist AMG487 suppressed both lipopolysaccharide-induced lung inflammation and vascular leakage in Ppard\n              <jats:sup>EC-KO<\/jats:sup>\n              mice.\n            <\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>CONCLUSIONS:<\/jats:title>\n            <jats:p>These results highlighted a novel anti-inflammatory role of PPAR\u03b4 in ECs by suppressing CXCL10-mediating vascular hyperpermeability. Targeting the CXCL10 signaling shows therapeutic potential against vascular injury in acute lung injury.<\/jats:p>\n          <\/jats:sec>","DOI":"10.1161\/circresaha.124.325855","type":"journal-article","created":{"date-parts":[[2025,2,25]],"date-time":"2025-02-25T10:00:52Z","timestamp":1740477652000},"page":"735-751","update-policy":"https:\/\/doi.org\/10.1161\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":26,"title":["Endothelial PPAR\u03b4 Ablation Exacerbates Vascular Hyperpermeability via STAT1\/CXCL10 Signaling in Acute Lung Injury"],"prefix":"10.1161","volume":"136","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-2242-5926","authenticated-orcid":true,"given":"Huiling","family":"Hong","sequence":"first","affiliation":[{"name":"School of Biomedical Sciences, CUHK Shenzhen Research Institute, Heart and Vascular Institute, CUHK-GIBH CAS Joint Research Laboratory on Stem Cell and Regenerative Medicine (H.H., Y.W., Y.L., Y.H., X.C., V.W.Y.W., X.Y.T.), The Chinese University of Hong Kong."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1092-7542","authenticated-orcid":true,"given":"Yalan","family":"Wu","sequence":"additional","affiliation":[{"name":"School of Biomedical Sciences, CUHK Shenzhen Research Institute, Heart and Vascular Institute, CUHK-GIBH CAS Joint Research Laboratory on Stem Cell and Regenerative Medicine (H.H., Y.W., Y.L., Y.H., X.C., V.W.Y.W., X.Y.T.), The Chinese University of Hong Kong."},{"name":"Department of Histology and Embryology, School of Basic Medical Sciences, Central South University, Changsha, China (Y.W.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0008-1413-9835","authenticated-orcid":true,"given":"Yangxian","family":"Li","sequence":"additional","affiliation":[{"name":"School of Biomedical Sciences, CUHK Shenzhen Research Institute, Heart and Vascular Institute, CUHK-GIBH CAS Joint Research Laboratory on Stem Cell and Regenerative Medicine (H.H., Y.W., Y.L., Y.H., X.C., V.W.Y.W., X.Y.T.), The Chinese University of Hong Kong."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0002-1158-8789","authenticated-orcid":true,"given":"Yumeng","family":"Han","sequence":"additional","affiliation":[{"name":"School of Biomedical Sciences, CUHK Shenzhen Research Institute, Heart and Vascular Institute, CUHK-GIBH CAS Joint Research Laboratory on Stem Cell and Regenerative Medicine (H.H., Y.W., Y.L., Y.H., X.C., V.W.Y.W., X.Y.T.), The Chinese University of Hong Kong."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6554-4285","authenticated-orcid":true,"given":"Xiaoyun","family":"Cao","sequence":"additional","affiliation":[{"name":"School of Biomedical Sciences, CUHK Shenzhen Research Institute, Heart and Vascular Institute, CUHK-GIBH CAS Joint Research Laboratory on Stem Cell and Regenerative Medicine (H.H., Y.W., Y.L., Y.H., X.C., V.W.Y.W., X.Y.T.), The Chinese University of Hong Kong."},{"name":"Department of Chemical Pathology (X.C., K.O.L., C.-K.W.), The Chinese University of Hong Kong."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0007-1948-5000","authenticated-orcid":true,"given":"Vivian Wei Yan","family":"Wu","sequence":"additional","affiliation":[{"name":"School of Biomedical Sciences, CUHK Shenzhen Research Institute, Heart and Vascular Institute, CUHK-GIBH CAS Joint Research Laboratory on Stem Cell and Regenerative Medicine (H.H., Y.W., Y.L., Y.H., X.C., V.W.Y.W., X.Y.T.), The Chinese University of Hong Kong."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thomas Ting Hei","family":"Chan","sequence":"additional","affiliation":[{"name":"School of Biomedical Sciences (T.T.H.C., J.Z., Q.C.), The Chinese University of Hong Kong."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9740-6159","authenticated-orcid":true,"given":"Jingying","family":"Zhou","sequence":"additional","affiliation":[{"name":"School of Biomedical Sciences (T.T.H.C., J.Z., Q.C.), The Chinese University of Hong Kong."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3106-562X","authenticated-orcid":true,"given":"Qin","family":"Cao","sequence":"additional","affiliation":[{"name":"School of Biomedical Sciences (T.T.H.C., J.Z., Q.C.), The Chinese University of Hong Kong."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1616-3643","authenticated-orcid":true,"given":"Kathy O.","family":"Lui","sequence":"additional","affiliation":[{"name":"Department of Chemical Pathology (X.C., K.O.L., C.-K.W.), The Chinese University of Hong Kong."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5637-8331","authenticated-orcid":true,"given":"Chun-Kwok","family":"Wong","sequence":"additional","affiliation":[{"name":"Department of Chemical Pathology (X.C., K.O.L., C.-K.W.), The Chinese University of Hong Kong."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2945-7923","authenticated-orcid":true,"given":"Zhiyu","family":"Dai","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, College of Medicine-Phoenix, University of Arizona (Z.D.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3472-9898","authenticated-orcid":true,"given":"Xiao Yu","family":"Tian","sequence":"additional","affiliation":[{"name":"School of Biomedical Sciences, CUHK Shenzhen Research Institute, Heart and Vascular Institute, CUHK-GIBH CAS Joint Research Laboratory on Stem Cell and Regenerative Medicine (H.H., Y.W., Y.L., Y.H., X.C., V.W.Y.W., X.Y.T.), The Chinese University of Hong Kong."}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"276","reference":[{"key":"e_1_3_3_2_2","doi-asserted-by":"publisher","DOI":"10.1001\/jama.2016.0287"},{"key":"e_1_3_3_3_2","doi-asserted-by":"publisher","DOI":"10.15252\/emmm.201810128"},{"key":"e_1_3_3_4_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(18)30696-2"},{"key":"e_1_3_3_5_2","doi-asserted-by":"publisher","DOI":"10.1213\/ane.0b013e318195e11d"},{"key":"e_1_3_3_6_2","doi-asserted-by":"publisher","DOI":"10.1093\/cvr\/cvaa070"},{"key":"e_1_3_3_7_2","doi-asserted-by":"publisher","DOI":"10.1111\/joim.12331"},{"key":"e_1_3_3_8_2","doi-asserted-by":"publisher","DOI":"10.1152\/physrev.00027.2013"},{"key":"e_1_3_3_9_2","doi-asserted-by":"publisher","DOI":"10.1177\/1753425918771748"},{"key":"e_1_3_3_10_2","doi-asserted-by":"publisher","DOI":"10.2353\/ajpath.2010.091010"},{"key":"e_1_3_3_11_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.resp.2014.04.004"},{"key":"e_1_3_3_12_2","doi-asserted-by":"publisher","DOI":"10.1007\/s00011-007-7157-4"},{"key":"e_1_3_3_13_2","doi-asserted-by":"publisher","DOI":"10.7150\/thno.69017"},{"key":"e_1_3_3_14_2","doi-asserted-by":"publisher","DOI":"10.7554\/eLife.53072"},{"key":"e_1_3_3_15_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.2211136119"},{"key":"e_1_3_3_16_2","doi-asserted-by":"publisher","DOI":"10.1172\/JCI60331"},{"key":"e_1_3_3_17_2","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCULATIONAHA.120.052318"},{"key":"e_1_3_3_18_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2020.01.015"},{"key":"e_1_3_3_19_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-020-2822-7"},{"key":"e_1_3_3_20_2","doi-asserted-by":"publisher","DOI":"10.1038\/nm.3888"},{"key":"e_1_3_3_21_2","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1101324"},{"key":"e_1_3_3_22_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.ajpath.2012.08.037"},{"key":"e_1_3_3_23_2","doi-asserted-by":"publisher","DOI":"10.1172\/JCI79668"},{"key":"e_1_3_3_24_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2022.01.014"},{"key":"e_1_3_3_25_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2020.10.037"},{"key":"e_1_3_3_26_2","doi-asserted-by":"publisher","DOI":"10.1038\/nri1604"},{"key":"e_1_3_3_27_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0021-9258(18)53303-2"},{"key":"e_1_3_3_28_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cytogfr.2011.06.001"},{"key":"e_1_3_3_29_2","doi-asserted-by":"publisher","DOI":"10.1084\/jem.20021897"},{"key":"e_1_3_3_30_2","doi-asserted-by":"publisher","DOI":"10.3389\/fcell.2018.00128"},{"key":"e_1_3_3_31_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.abi5200"},{"key":"e_1_3_3_32_2","doi-asserted-by":"publisher","DOI":"10.1164\/rccm.201002-0240OC"},{"key":"e_1_3_3_33_2","doi-asserted-by":"publisher","DOI":"10.1016\/s0014-2999(01)01589-8"},{"key":"e_1_3_3_34_2","doi-asserted-by":"publisher","DOI":"10.1161\/ATVBAHA.107.149815"},{"key":"e_1_3_3_35_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41591-020-1038-6"},{"key":"e_1_3_3_36_2","doi-asserted-by":"publisher","DOI":"10.1186\/s13054-020-03328-0"},{"key":"e_1_3_3_37_2","doi-asserted-by":"publisher","DOI":"10.1128\/CMR.00299-20"},{"key":"e_1_3_3_38_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.jhep.2014.07.006"},{"key":"e_1_3_3_39_2","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2006-08-040337"},{"key":"e_1_3_3_40_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.ctrv.2017.11.007"},{"key":"e_1_3_3_41_2","doi-asserted-by":"publisher","DOI":"10.1172\/jci.insight.98911"},{"key":"e_1_3_3_42_2","doi-asserted-by":"publisher","DOI":"10.1186\/cc13902"},{"key":"e_1_3_3_43_2","doi-asserted-by":"publisher","DOI":"10.1164\/rccm.201108-1560OC"},{"key":"e_1_3_3_44_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M111384200"},{"key":"e_1_3_3_45_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M109.016766"},{"key":"e_1_3_3_46_2","doi-asserted-by":"publisher","DOI":"10.1128\/JVI.02738-13"},{"key":"e_1_3_3_47_2","doi-asserted-by":"publisher","DOI":"10.1002\/glia.22857"},{"key":"e_1_3_3_48_2","doi-asserted-by":"publisher","DOI":"10.1002\/jcb.24118"},{"key":"e_1_3_3_49_2","doi-asserted-by":"publisher","DOI":"10.1038\/ncb1486"},{"key":"e_1_3_3_50_2","doi-asserted-by":"publisher","DOI":"10.1097\/SHK.0000000000000473"},{"key":"e_1_3_3_51_2","doi-asserted-by":"publisher","DOI":"10.1172\/JCI93868"},{"key":"e_1_3_3_52_2","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2022-163863"},{"key":"e_1_3_3_53_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.phrs.2014.05.011"},{"key":"e_1_3_3_54_2","doi-asserted-by":"publisher","DOI":"10.1038\/nprot.2008.214"},{"key":"e_1_3_3_55_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2019.05.031"},{"key":"e_1_3_3_56_2","doi-asserted-by":"publisher","DOI":"10.1038\/nbt.3192"},{"key":"e_1_3_3_57_2","doi-asserted-by":"publisher","DOI":"10.1186\/1471-2105-14-7"},{"key":"e_1_3_3_58_2","unstructured":"Kolde R. Pheatmap: pretty heatmaps. R package version 1.0.12. Accessed January 4 2019. https:\/\/cran.r-project.org\/web\/packages\/pheatmap\/index.html"},{"key":"e_1_3_3_59_2","doi-asserted-by":"publisher","DOI":"10.1186\/s12859-015-0701-2"},{"key":"e_1_3_3_60_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.jhep.2015.09.005"},{"key":"e_1_3_3_61_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.chest.2018.03.003"}],"container-title":["Circulation Research"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.ahajournals.org\/doi\/full\/10.1161\/CIRCRESAHA.124.325855","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,3,27]],"date-time":"2025-03-27T18:18:39Z","timestamp":1743099519000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.ahajournals.org\/doi\/10.1161\/CIRCRESAHA.124.325855"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,3,28]]},"references-count":60,"journal-issue":{"issue":"7","published-print":{"date-parts":[[2025,3,28]]}},"alternative-id":["10.1161\/CIRCRESAHA.124.325855"],"URL":"https:\/\/doi.org\/10.1161\/circresaha.124.325855","relation":{},"ISSN":["0009-7330","1524-4571"],"issn-type":[{"value":"0009-7330","type":"print"},{"value":"1524-4571","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,3,28]]},"assertion":[{"value":"2024-11-12","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2025-01-16","order":1,"name":"revised","label":"Revised","group":{"name":"publication_history","label":"Publication History"}},{"value":"2025-02-11","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2025-02-25","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}