{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,22]],"date-time":"2026-10-22T13:10:50Z","timestamp":1792674650795,"version":"4.5.0"},"reference-count":35,"publisher":"Oxford University Press (OUP)","issue":"3","license":[{"start":{"date-parts":[[2014,3,1]],"date-time":"2014-03-01T00:00:00Z","timestamp":1393632000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/pages\/standard-publication-reuse-rights"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2014,3,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Kr\u00fcppel-like factor 4 (KLF4) is a transcription factor expressed in the vascular endothelium, where it promotes anti-inflammatory and anticoagulant states, and increases endothelial nitric oxide synthase expression. We examined the role of endothelial KLF4 in pulmonary arterial (PA) hypertension (PAH). Mice with endothelial KLF4 knockdown were exposed to hypoxia for 3 weeks, followed by measurement of right ventricular and PA pressures, pulmonary vascular muscularization, and right ventricular hypertrophy. The effect of KLF4 on target gene expression was assessed in lungs from these mice, verified in vitro by small interfering RNA (siRNA) knockdown of KLF4, and further studied at the promoter level with cotransfection experiments. KLF4 expression was measured in lung tissue from patients with PAH and normal control subjects. We found that, after hypoxia, right ventricular and PA pressures were significantly higher in KLF4 knockdown animals than controls. Knockdown animals also had more severe pulmonary vascular muscularization and right ventricular hypertrophy. KLF4 knockdown resulted in increased pulmonary expression of endothelin-1 and decreased expression of endothelial nitric oxide synthase, endothelin receptor subtype B, and prostacyclin synthase. Concordant findings were observed in vitro, both with siRNA knockdown of KLF4 and promoter activity assays. Finally, KLF4 expression was reduced in lungs from patients with PAH. In conclusion, endothelial KLF4 regulates the transcription of genes involved in key pathways implicated in PAH, and its loss exacerbates pulmonary hypertension in response to chronic hypoxia in mice. These results introduce a novel transcriptional modulator of PAH, with the potential of becoming a new therapeutic target.<\/jats:p>","DOI":"10.1165\/rcmb.2013-0135oc","type":"journal-article","created":{"date-parts":[[2013,10,24]],"date-time":"2013-10-24T17:42:43Z","timestamp":1382636563000},"page":"647-653","source":"Crossref","is-referenced-by-count":58,"title":["Endothelial Kr\u00fcppel-Like Factor 4 Modulates Pulmonary Arterial Hypertension"],"prefix":"10.1093","volume":"50","author":[{"given":"Mohammad A.","family":"Shatat","sequence":"first","affiliation":[{"name":"Division of Pulmonary, Critical Care and Sleep Medicine, Department of Medicine, Case Western Reserve University, and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hongmei","family":"Tian","sequence":"additional","affiliation":[{"name":"Case Cardiovascular Research Institute, Case Western Reserve University, and Harrington Heart and Vascular Institute, University Hospitals Case Medical Center, Cleveland, Ohio"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rongli","family":"Zhang","sequence":"additional","affiliation":[{"name":"Case Cardiovascular Research Institute, Case Western Reserve University, and Harrington Heart and Vascular Institute, University Hospitals Case Medical Center, Cleveland, Ohio"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gaurav","family":"Tandon","sequence":"additional","affiliation":[{"name":"Department of Medicine, University Hospitals Case Medical Center, Cleveland, Ohio"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrew","family":"Hale","sequence":"additional","affiliation":[{"name":"Case Cardiovascular Research Institute, Case Western Reserve University, and Harrington Heart and Vascular Institute, University Hospitals Case Medical Center, Cleveland, Ohio"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jason 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and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cristina","family":"Rodr\u00edguez","sequence":"additional","affiliation":[{"name":"Cardiovascular Research Center, Consell Superior d'Investigacions Cient\u00edfiques i l'Institut Catal\u00e0 de Ci\u00e8ncies Cardiovasculars (CSIC\u2013ICCC), Institute of Biomedical Research (IIB\u2013Sant Pau), Barcelona, Spain; and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hunter C.","family":"Champion","sequence":"additional","affiliation":[{"name":"Department of Medicine, Cardiovascular Institute, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mukesh K.","family":"Jain","sequence":"additional","affiliation":[{"name":"Case Cardiovascular Research Institute, Case Western Reserve University, and Harrington Heart and Vascular Institute, University Hospitals Case Medical Center, Cleveland, Ohio"},{"name":"Department of Medicine, University Hospitals Case Medical Center, Cleveland, Ohio"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anne","family":"Hamik","sequence":"additional","affiliation":[{"name":"Case Cardiovascular Research Institute, Case Western Reserve University, and Harrington Heart and Vascular Institute, University Hospitals Case Medical Center, Cleveland, Ohio"},{"name":"Department of Medicine, University Hospitals Case Medical Center, Cleveland, Ohio"},{"name":"the Louis Stokes Cleveland Veterans Affairs Medical Center, Cleveland, Ohio"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2014,3,1]]},"reference":[{"key":"2026030623192724300_bib1","doi-asserted-by":"crossref","first-page":"1573","DOI":"10.1016\/j.jacc.2009.01.004","article-title":"ACCF\/AHA 2009 expert consensus document on pulmonary hypertension a report of the American College of Cardiology Foundation Task Force on Expert Consensus Documents and the 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