{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,22]],"date-time":"2026-09-22T04:01:15Z","timestamp":1790049675782,"version":"4.0.1"},"reference-count":43,"publisher":"Oxford University Press (OUP)","issue":"1","license":[{"start":{"date-parts":[[2017,9,28]],"date-time":"2017-09-28T00:00:00Z","timestamp":1506556800000},"content-version":"vor","delay-in-days":1,"URL":"https:\/\/academic.oup.com\/journals\/pages\/open_access\/funder_policies\/chorus\/standard_publication_model"}],"funder":[{"DOI":"10.13039\/100000002","name":"NIH","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000098","name":"NIH Clinical Center","doi-asserted-by":"publisher","award":["NCT01730092"],"award-info":[{"award-number":["NCT01730092"]}],"id":[{"id":"10.13039\/100000098","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2018,1,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:sec>\n                  <jats:title>Aims<\/jats:title>\n                  <jats:p>Spironolactone (SPL) improves endothelial dysfunction and survival in heart failure. Immune modulation, including poorly understood mineralocorticoid receptor (MR)-independent effects of SPL might contribute to these benefits and possibly be useful in other inflammatory cardiovascular diseases such as pulmonary arterial hypertension.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Methods and results<\/jats:title>\n                  <jats:p>Using human embryonic kidney cells (HEK 293) expressing specific nuclear receptors, SPL suppressed NF-\u03baB and AP-1 reporter activity independent of MR and other recognized nuclear receptor partners. NF-\u03baB and AP-1 DNA binding were not affected by SPL and protein synthesis blockade did not interfere with SPL-induced suppression of inflammatory signalling. In contrast, proteasome blockade to inhibit degradation of xeroderma pigmentosum group B complementing protein (XPB), a subunit of the general transcription factor TFIIH, or XPB overexpression both prevented SPL-mediated suppression of inflammation. Similar to HEK 293 cells, a proteasome inhibitor blocked XPB loss and SPL suppression of AP-1 induced target genes in human pulmonary artery endothelial cells (PAECs). Unlike SPL, eplerenone (EPL) did not cause XPB degradation and failed to similarly suppress inflammatory signalling. SPL combined with siRNA XPB knockdown further reduced XPB protein levels and had the greatest effect on PAEC inflammatory gene transcription. Using chromatin-immunoprecipitation, PAEC target gene susceptibility to SPL was associated with low basal RNA polymerase II (RNAPII) occupancy and TNF\u03b1-induced RNAPII and XPB recruitment. XP patient-derived fibroblasts carrying an N-terminal but not C-terminal XPB mutations were insensitive to both SPL-mediated XPB degradation and TNF\u03b1-induced target gene suppression. Importantly, SPL treatment decreased whole lung XPB protein levels in a monocrotaline rat model of pulmonary hypertension and reduced inflammatory markers in an observational cohort of PAH patients.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Conclusion<\/jats:title>\n                  <jats:p>SPL has important anti-inflammatory effects independent of aldosterone and MR, not shared with EPL. Drug-induced, proteasome-dependent XPB degradation may be a useful therapeutic approach in cardiovascular diseases driven by inflammation.<\/jats:p>\n               <\/jats:sec>","DOI":"10.1093\/cvr\/cvx198","type":"journal-article","created":{"date-parts":[[2017,9,26]],"date-time":"2017-09-26T07:09:24Z","timestamp":1506409764000},"page":"65-76","source":"Crossref","is-referenced-by-count":35,"title":["Spironolactone-induced degradation of the TFIIH core complex XPB subunit suppresses NF-\u03baB and AP-1 signalling"],"prefix":"10.1093","volume":"114","author":[{"given":"Jason M","family":"Elinoff","sequence":"first","affiliation":[{"name":"Critical Care Medicine Department, Clinical Center, 10 Center Drive, Room 2C145, Bethesda, MD 20892-1662, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Li-Yuan","family":"Chen","sequence":"additional","affiliation":[{"name":"Critical Care Medicine Department, Clinical Center, 10 Center Drive, Room 2C145, Bethesda, MD 20892-1662, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Edward J","family":"Dougherty","sequence":"additional","affiliation":[{"name":"Critical Care Medicine Department, Clinical Center, 10 Center Drive, Room 2C145, Bethesda, MD 20892-1662, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Keytam S","family":"Awad","sequence":"additional","affiliation":[{"name":"Critical Care Medicine Department, Clinical Center, 10 Center Drive, Room 2C145, Bethesda, MD 20892-1662, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shuibang","family":"Wang","sequence":"additional","affiliation":[{"name":"Critical Care Medicine Department, Clinical Center, 10 Center Drive, Room 2C145, Bethesda, MD 20892-1662, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Angelique","family":"Biancotto","sequence":"additional","affiliation":[{"name":"Center for Human Immunology, Autoimmunity, and Inflammation, 10 Center Drive, Room 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USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Junfeng","family":"Sun","sequence":"additional","affiliation":[{"name":"Critical Care Medicine Department, Clinical Center, 10 Center Drive, Room 2C145, Bethesda, MD 20892-1662, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ioana R","family":"Preston","sequence":"additional","affiliation":[{"name":"Tupper Research Institute and Pulmonary, Critical Care, and Sleep Division, Tufts Medical Center, Boston, MA 02111, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael A","family":"Solomon","sequence":"additional","affiliation":[{"name":"Critical Care Medicine Department, Clinical Center, 10 Center Drive, Room 2C145, Bethesda, MD 20892-1662, USA"},{"name":"Cardiovascular and Pulmonary Branch, National Heart, Lung and Blood Institute, National Institutes of Health, 10 Center Drive, Room 2C145, Bethesda, MD 20892-1662, 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