{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,6]],"date-time":"2026-10-06T11:07:27Z","timestamp":1791284847249,"version":"4.1.0"},"reference-count":51,"publisher":"MDPI AG","issue":"1","license":[{"start":{"date-parts":[[2022,12,29]],"date-time":"2022-12-29T00:00:00Z","timestamp":1672272000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"American Heart Association Scientist Development","award":["15SDG24910003"],"award-info":[{"award-number":["15SDG24910003"]}]},{"name":"American Heart Association Scientist Development","award":["18IPA34170257"],"award-info":[{"award-number":["18IPA34170257"]}]},{"name":"American Heart Association Scientist Development","award":["RG-515656"],"award-info":[{"award-number":["RG-515656"]}]},{"name":"American Heart Association Innovator","award":["15SDG24910003"],"award-info":[{"award-number":["15SDG24910003"]}]},{"name":"American Heart Association Innovator","award":["18IPA34170257"],"award-info":[{"award-number":["18IPA34170257"]}]},{"name":"American Heart Association Innovator","award":["RG-515656"],"award-info":[{"award-number":["RG-515656"]}]},{"name":"American Lung Association Biomedical Research","award":["15SDG24910003"],"award-info":[{"award-number":["15SDG24910003"]}]},{"name":"American Lung Association Biomedical Research","award":["18IPA34170257"],"award-info":[{"award-number":["18IPA34170257"]}]},{"name":"American Lung Association Biomedical Research","award":["RG-515656"],"award-info":[{"award-number":["RG-515656"]}]},{"name":"Gilead Sciences Research Scholars Program in Pulmonary Arterial Hypertension","award":["15SDG24910003"],"award-info":[{"award-number":["15SDG24910003"]}]},{"name":"Gilead Sciences Research Scholars Program in Pulmonary Arterial Hypertension","award":["18IPA34170257"],"award-info":[{"award-number":["18IPA34170257"]}]},{"name":"Gilead Sciences Research Scholars Program in Pulmonary Arterial Hypertension","award":["RG-515656"],"award-info":[{"award-number":["RG-515656"]}]},{"name":"Vitalant and the Hemophilia Center of Western Pennsylvania","award":["15SDG24910003"],"award-info":[{"award-number":["15SDG24910003"]}]},{"name":"Vitalant and the Hemophilia Center of Western Pennsylvania","award":["18IPA34170257"],"award-info":[{"award-number":["18IPA34170257"]}]},{"name":"Vitalant and the Hemophilia Center of Western Pennsylvania","award":["RG-515656"],"award-info":[{"award-number":["RG-515656"]}]},{"name":"Pittsburgh Heart, Lung, and Blood Vascular Medicine Institute","award":["15SDG24910003"],"award-info":[{"award-number":["15SDG24910003"]}]},{"name":"Pittsburgh Heart, Lung, and Blood Vascular Medicine Institute","award":["18IPA34170257"],"award-info":[{"award-number":["18IPA34170257"]}]},{"name":"Pittsburgh Heart, Lung, and Blood Vascular Medicine Institute","award":["RG-515656"],"award-info":[{"award-number":["RG-515656"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Antioxidants"],"abstract":"<jats:p>Pulmonary arterial hypertension (PAH) is a rare yet devastating and incurable disease with few treatment options. The underlying mechanisms of PAH appear to involve substantial cellular proliferation and vascular remodeling, causing right ventricular overload and eventual heart failure. Recent evidence suggests a significant seminal role of the pulmonary endothelium in the initiation and promotion of PAH. Our previous work identified elevated reactive oxygen species (ROS)-producing enzyme NADPH oxidase 1 (NOX1) in human pulmonary artery endothelial cells (HPAECs) of PAH patients promoting endothelial cell proliferation in vitro. In this study, we interrogated chemokine CXCL12\u2032s (aka SDF-1) role in EC proliferation under the control of NOX1 and specificity protein 1 (Sp1). We report here that NOX1 can drive hypoxia-induced endothelial CXCL12 expression via the transcription factor Sp1 leading to HPAEC proliferation and migration. Indeed, NOX1 drove hypoxia-induced Sp1 activation, along with an increased capacity of Sp1 to bind cognate promoter regions in the CXCL12 promoter. Sp1 activation induced elevated expression of CXCL12 in hypoxic HPAECs, supporting downstream induction of expression at the CXCL12 promoter via NOX1 activity. Pathological levels of CXCL12 mimicking those reported in human PAH patient serum restored EC proliferation impeded by specific NOX1 inhibitor. The translational relevance of our findings is highlighted by elevated NOX1 activity, Sp1 activation, and CXCL12 expression in explanted lung samples from PAH patients compared to non-PAH controls. Analysis of phosphofructokinase, glucose-6-phosphate dehydrogenase, and glutaminase activity revealed that CXCL12 induces glutamine and glucose metabolism, which are foundational to EC cell proliferation. Indeed, in explanted human PAH lungs, demonstrably higher glutaminase activity was detected compared to healthy controls. Finally, infusion of recombinant CXCL12 into healthy mice amplified pulmonary arterial pressure, right ventricle remodeling, and elevated glucose and glutamine metabolism. Together these data suggest a central role for a novel NOX1-Sp1-CXCL12 pathway in mediating PAH phenotype in the lung endothelium.<\/jats:p>","DOI":"10.3390\/antiox12010071","type":"journal-article","created":{"date-parts":[[2022,12,30]],"date-time":"2022-12-30T03:31:17Z","timestamp":1672371077000},"page":"71","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":20,"title":["Specificity Protein 1-Mediated Promotion of CXCL12 Advances Endothelial Cell Metabolism and Proliferation in Pulmonary Hypertension"],"prefix":"10.3390","volume":"12","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-0173-3188","authenticated-orcid":false,"given":"Evan R.","family":"DeVallance","sequence":"first","affiliation":[{"name":"Department of Physiology and Pharmacology, West Virginia University School of Medicine, Morgantown, WV 26506, USA"},{"name":"Center for Inhalation Toxicology, West Virginia University School of Medicine, Morgantown, WV 26506, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christopher M.","family":"Dustin","sequence":"additional","affiliation":[{"name":"Pittsburgh Heart, Lung, Blood and Vascular Medicine Institute, University of Pittsburgh, Pittsburgh, PA 15261, USA"},{"name":"Department of Pharmacology and Chemical Biology, University of Pittsburgh, Pittsburgh, PA 15261, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniel Simoes","family":"de Jesus","sequence":"additional","affiliation":[{"name":"William Harvey Research Institute, Barts & The London School of Medicine and Dentistry, Queen Mary University of London, London EC1M 6BQ, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0386-5360","authenticated-orcid":false,"given":"Imad Al","family":"Ghouleh","sequence":"additional","affiliation":[{"name":"Pittsburgh Heart, Lung, Blood and Vascular Medicine Institute, University of Pittsburgh, Pittsburgh, PA 15261, USA"},{"name":"Department of Cardiology, University of Pittsburgh, Pittsburgh, PA 15261, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"John C.","family":"Sembrat","sequence":"additional","affiliation":[{"name":"Division of Pulmonary, Allergy, and Critical Care Medicine, University of Pittsburgh, Pittsburgh, PA 15261, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2482-080X","authenticated-orcid":false,"given":"Eugenia","family":"Cifuentes-Pagano","sequence":"additional","affiliation":[{"name":"Pittsburgh Heart, Lung, Blood and Vascular Medicine Institute, University of Pittsburgh, Pittsburgh, PA 15261, USA"},{"name":"Department of Pharmacology and Chemical Biology, University of Pittsburgh, Pittsburgh, PA 15261, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Patrick J.","family":"Pagano","sequence":"additional","affiliation":[{"name":"Pittsburgh Heart, Lung, Blood and Vascular Medicine Institute, University of Pittsburgh, Pittsburgh, PA 15261, USA"},{"name":"Department of Pharmacology and Chemical Biology, University of Pittsburgh, Pittsburgh, PA 15261, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2022,12,29]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1043","DOI":"10.1378\/chest.15-0300","article-title":"Five-Year Outcomes of Patients Enrolled in the REVEAL Registry","volume":"148","author":"Farber","year":"2015","journal-title":"Chest"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"7","DOI":"10.3322\/caac.21442","article-title":"Cancer statistics, 2018","volume":"68","author":"Siegel","year":"2018","journal-title":"CA Cancer J. 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