{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,8]],"date-time":"2026-09-08T11:29:26Z","timestamp":1788866966210,"version":"build-2803163510"},"reference-count":55,"publisher":"MDPI AG","issue":"19","license":[{"start":{"date-parts":[[2021,9,26]],"date-time":"2021-09-26T00:00:00Z","timestamp":1632614400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100008593","name":"European Respiratory Society","doi-asserted-by":"publisher","award":["201801-00318"],"award-info":[{"award-number":["201801-00318"]}],"id":[{"id":"10.13039\/100008593","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001655","name":"German Academic Exchange Service","doi-asserted-by":"publisher","award":["91656598"],"award-info":[{"award-number":["91656598"]}],"id":[{"id":"10.13039\/501100001655","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001659","name":"Deutsche Forschungsgemeinschaft","doi-asserted-by":"publisher","award":["268555672"],"award-info":[{"award-number":["268555672"]}],"id":[{"id":"10.13039\/501100001659","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Excellence Cluster Cardio-Pulmonary Institute","award":["390649896"],"award-info":[{"award-number":["390649896"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Increased proliferation of pulmonary arterial smooth muscle cells (PASMCs) in response to chronic hypoxia contributes to pulmonary vascular remodeling in pulmonary hypertension (PH). PH shares numerous similarities with cancer, including a metabolic shift towards glycolysis. In lung cancer, adenylate kinase 4 (AK4) promotes metabolic reprogramming and metastasis. Against this background, we show that AK4 regulates cell proliferation and energy metabolism of primary human PASMCs. We demonstrate that chronic hypoxia upregulates AK4 in PASMCs in a hypoxia-inducible factor-1\u03b1 (HIF-1\u03b1)-dependent manner. RNA interference of AK4 decreases the viability and proliferation of PASMCs under both normoxia and chronic hypoxia. AK4 silencing in PASMCs augments mitochondrial respiration and reduces glycolytic metabolism. The observed effects are associated with reduced levels of phosphorylated protein kinase B (Akt) as well as HIF-1\u03b1, indicating the existence of an AK4-HIF-1\u03b1 feedforward loop in hypoxic PASMCs. Finally, we show that AK4 levels are elevated in pulmonary vessels from patients with idiopathic pulmonary arterial hypertension (IPAH), and AK4 silencing decreases glycolytic metabolism of IPAH-PASMCs. We conclude that AK4 is a new metabolic regulator in PASMCs interacting with HIF-1\u03b1 and Akt signaling pathways to drive the pro-proliferative and glycolytic phenotype of PH.<\/jats:p>","DOI":"10.3390\/ijms221910371","type":"journal-article","created":{"date-parts":[[2021,9,27]],"date-time":"2021-09-27T04:55:33Z","timestamp":1632718533000},"page":"10371","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":41,"title":["Adenylate Kinase 4\u2014A Key Regulator of Proliferation and Metabolic Shift in Human Pulmonary Arterial Smooth Muscle Cells via Akt and HIF-1\u03b1 Signaling Pathways"],"prefix":"10.3390","volume":"22","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-4243-8161","authenticated-orcid":false,"given":"Magdalena","family":"Wujak","sequence":"first","affiliation":[{"name":"Universities of Giessen and Marburg Lung Center (UGMLC), German Center for Lung Research (DZL), Excellence Cluster Cardio-Pulmonary Institute (CPI), Justus-Liebig University, 35392 Giessen, Germany"},{"name":"Department of Medicinal Chemistry, Collegium Medicum in Bydgoszcz, Faculty of Pharmacy, Nicolaus Copernicus University in Toru\u0144, 85-089 Bydgoszcz, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christine","family":"Veith","sequence":"additional","affiliation":[{"name":"Universities of Giessen and Marburg Lung Center (UGMLC), German Center for Lung Research (DZL), Excellence Cluster Cardio-Pulmonary Institute (CPI), Justus-Liebig University, 35392 Giessen, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2788-8586","authenticated-orcid":false,"given":"Cheng-Yu","family":"Wu","sequence":"additional","affiliation":[{"name":"Universities of Giessen and Marburg Lung Center (UGMLC), German Center for Lung Research (DZL), Excellence Cluster Cardio-Pulmonary Institute (CPI), Justus-Liebig University, 35392 Giessen, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tessa","family":"Wilke","sequence":"additional","affiliation":[{"name":"Universities of Giessen and Marburg Lung Center (UGMLC), German Center for Lung Research (DZL), Excellence Cluster Cardio-Pulmonary Institute (CPI), Justus-Liebig University, 35392 Giessen, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zeki Ilker","family":"Kanbagli","sequence":"additional","affiliation":[{"name":"Universities of Giessen and Marburg Lung Center (UGMLC), German Center for Lung Research (DZL), Excellence Cluster Cardio-Pulmonary Institute (CPI), Justus-Liebig University, 35392 Giessen, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tatyana","family":"Novoyatleva","sequence":"additional","affiliation":[{"name":"Universities of Giessen and Marburg Lung Center (UGMLC), German Center for Lung Research (DZL), Excellence Cluster Cardio-Pulmonary Institute (CPI), Justus-Liebig University, 35392 Giessen, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andreas","family":"Guenther","sequence":"additional","affiliation":[{"name":"Universities of Giessen and Marburg Lung Center (UGMLC), German Center for Lung Research (DZL), Excellence Cluster Cardio-Pulmonary Institute (CPI), Justus-Liebig University, 35392 Giessen, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1946-0894","authenticated-orcid":false,"given":"Werner","family":"Seeger","sequence":"additional","affiliation":[{"name":"Universities of Giessen and Marburg Lung Center (UGMLC), German Center for Lung Research (DZL), Excellence Cluster Cardio-Pulmonary Institute (CPI), Justus-Liebig University, 35392 Giessen, Germany"},{"name":"Department of Internal Medicine, Universities of Giessen and Marburg Lung Center (UGMLC), Institute for Lung Health (ILH), Cardio-Pulmonary Institute (CPI), German Center for Lung Research (DZL), 35392 Giessen, Germany"},{"name":"Department of Lung Development and Remodelling, Max-Planck Institute for Heart and Lung Research, 61231 Bad Nauheim, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Friedrich","family":"Grimminger","sequence":"additional","affiliation":[{"name":"Universities of Giessen and Marburg Lung Center (UGMLC), German Center for Lung Research (DZL), Excellence Cluster Cardio-Pulmonary Institute (CPI), Justus-Liebig University, 35392 Giessen, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Natascha","family":"Sommer","sequence":"additional","affiliation":[{"name":"Universities of Giessen and Marburg Lung Center (UGMLC), German Center for Lung Research (DZL), Excellence Cluster Cardio-Pulmonary Institute (CPI), Justus-Liebig University, 35392 Giessen, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ralph Theo","family":"Schermuly","sequence":"additional","affiliation":[{"name":"Universities 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