{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,24]],"date-time":"2026-07-24T19:25:54Z","timestamp":1784921154776,"version":"3.55.0"},"reference-count":42,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"6","license":[{"start":{"date-parts":[[2021,4,19]],"date-time":"2021-04-19T00:00:00Z","timestamp":1618790400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"},{"start":{"date-parts":[[2021,4,19]],"date-time":"2021-04-19T00:00:00Z","timestamp":1618790400000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"content-domain":{"domain":["lww.com","ovid.com"],"crossmark-restriction":true},"short-container-title":["Hepatology"],"published-print":{"date-parts":[[2021,6]]},"abstract":"<jats:sec>\n            <jats:title>Background and Aims<\/jats:title>\n            <jats:p>During liver fibrosis, liver sinusoidal endothelial cells (LSECs) release angiocrine signals to recruit inflammatory cells into the liver. p300, a master regulator of gene transcription, is associated with pathological inflammatory response. Therefore, we examined how endothelial p300 regulates angiocrine signaling and inflammation related to portal hypertension and fibrogenesis.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Approach and Results<\/jats:title>\n            <jats:p>CCl<jats:sub>4<\/jats:sub> or partial inferior vena cava ligation (pIVCL) was used to induce liver injury. Mice with LSEC\u2010specific <jats:italic toggle=\"yes\">p300<\/jats:italic> deletion (<jats:italic toggle=\"yes\">p300<\/jats:italic>\n                                 <jats:sup>LSEC\u0394\/\u0394<\/jats:sup>) or C\u2010C motif chemokine ligand 2 (<jats:italic toggle=\"yes\">Ccl2<\/jats:italic>) deficiency, nuclear factor kappa B (<jats:italic toggle=\"yes\">NF\u03baB<\/jats:italic>)\u2013<jats:italic toggle=\"yes\">p50<\/jats:italic> knockout mice, and bromodomain containing 4 (BRD4) inhibitors in wild\u2010type mice were used to investigate mechanisms of inflammation regulation. Leukocytes were analyzed by mass cytometry by time\u2010of\u2010flight. Epigenetic histone marks were modified by CRISPR endonuclease\u2010deficient CRISPR\u2010associated 9\u2010fused with the Kr\u00fcppel associated box domain (CRISPR\u2010dCas9\u2010KRAB)\u2013mediated epigenome editing. Portal pressure and liver fibrosis were reduced in <jats:italic toggle=\"yes\">p300<\/jats:italic>\n                                 <jats:sup>LSEC\u0394\/\u0394<\/jats:sup> mice compared to <jats:italic toggle=\"yes\">p300<\/jats:italic>\n                                 <jats:sup>fl\/fl<\/jats:sup> mice following liver injury. Accumulation of macrophages was also reduced in <jats:italic toggle=\"yes\">p300<\/jats:italic>\n                                 <jats:sup>LSEC\u0394\/\u0394<\/jats:sup> mouse livers. <jats:italic toggle=\"yes\">Ccl2<\/jats:italic> was the most up\u2010regulated chemokine in injured LSECs, but its increase was abrogated in <jats:italic toggle=\"yes\">p300<\/jats:italic>\n                                 <jats:sup>LSEC\u0394\/\u0394<\/jats:sup> mice. While the macrophage accumulation was increased in <jats:italic toggle=\"yes\">NF\u03baB\u2010p50<\/jats:italic> knockout mice with enhanced NF\u03baB activity, it was reduced in mice with LSEC\u2010specific <jats:italic toggle=\"yes\">Ccl2<\/jats:italic> deficiency and mice treated with specific BRD4 inhibitors. <jats:italic toggle=\"yes\">In vitro<\/jats:italic>, epigenome editing of <jats:italic toggle=\"yes\">CCL2<\/jats:italic> enhancer and promoter regions by CRISPR\u2010dCas9\u2010KRAB technology repressed TNF\u03b1\u2010induced <jats:italic toggle=\"yes\">CCL2<\/jats:italic> transcription through H3K9 trimethylation. In contrast, TNF\u03b1 activated <jats:italic toggle=\"yes\">CCL2<\/jats:italic> transcription by promoting p300 interaction with NF\u03baB and BRD4, leading to histone H3 lysine 27 acetylation at <jats:italic toggle=\"yes\">CCL2<\/jats:italic> enhancer and promoter regions.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Conclusions<\/jats:title>\n            <jats:p>In summary, endothelial p300 interaction with NF\u03baB and BRD4 increases <jats:italic toggle=\"yes\">CCL2<\/jats:italic> expression, leading to macrophage accumulation, portal hypertension, and liver fibrosis. Inhibition of p300 and its binding partners might serve as therapy in the treatment of liver diseases.<\/jats:p>\n          <\/jats:sec>","DOI":"10.1002\/hep.31617","type":"journal-article","created":{"date-parts":[[2020,11,7]],"date-time":"2020-11-07T12:08:01Z","timestamp":1604750881000},"page":"2468-2483","update-policy":"https:\/\/doi.org\/10.1097\/lww.0000000000001000","source":"Crossref","is-referenced-by-count":93,"title":["Endothelial p300 Promotes Portal Hypertension and Hepatic Fibrosis Through C\u2010C Motif Chemokine Ligand 2\u2013Mediated Angiocrine Signaling"],"prefix":"10.1097","volume":"73","author":[{"given":"Jinhang","family":"Gao","sequence":"first","affiliation":[{"name":"Division of Gastroenterology and Hepatology,Mayo Clinic,Rochester,MN"},{"name":"Laboratory of Gastroenterology and Hepatology,West China Hospital,Sichuan 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