{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,7,30]],"date-time":"2025-07-30T16:15:08Z","timestamp":1753892108332,"version":"3.41.2"},"reference-count":39,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2022,8,12]],"date-time":"2022-08-12T00:00:00Z","timestamp":1660262400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Pharmacol."],"abstract":"<jats:p>Acute pulmonary embolism (APE) is a debilitating condition with high incidence and mortality rates. APE is widely treated with the serine protease urokinase or urokinase-type plasminogen activator (uPA) that functions by resolving blood clots <jats:italic>via<\/jats:italic> catalyzing the conversion of plasminogen to plasmin. Treatment with recombinant uPA has been shown to increase endogenous expression of uPA and its cognate receptor, uPAR; however, the mechanisms for this induction are not known. Using an <jats:italic>in vitro<\/jats:italic> hypoxia\/reoxygenation model in bronchial epithelial BEAS-2B cells, we show that induction of hypoxia\/reoxygenation induces apoptosis and increases secretion of tumor necrosis factor\u2013alpha, brain natriuretic peptide, and fractalkine, which are attenuated when treated with exogenous uPA. Induction of hypoxia\/reoxygenation resulted in decreased expression of uPAR on cell surface without any significant changes in its messenger RNA expression, highlighting post-transcriptional regulatory mechanisms. Determination of uPAR protein half-life using cycloheximide showed treatment with uPA significantly increased its half-life (209.6 \u00b1 0.2\u00a0min from 48.2 \u00b1 2.3\u00a0min). Hypoxia\/reoxygenation promoted the degradation of uPAR. Inhibition of proteasome-mediated degradation using MG-132 and lactacystin revealed that uPAR was actively degraded when hypoxia\/reoxygenation was induced and that it was reversed when treated with exogenous uPA. Determination of the proteolytic activity of 20S proteasome showed a global increase in ubiquitin\u2013proteasome activation without an increase in proteasome content in cells subjected to hypoxia\/reoxygenation. Our results cumulatively reveal that uPAR is actively degraded following hypoxia\/reoxygenation, and the degradation was significantly weakened by exogenous uPA treatment. Given the importance of the uPA\/uPAR axis in a multitude of pathophysiological contexts, these findings provide important yet undefined mechanistic insights.<\/jats:p>","DOI":"10.3389\/fphar.2022.754271","type":"journal-article","created":{"date-parts":[[2022,8,12]],"date-time":"2022-08-12T04:37:14Z","timestamp":1660279034000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Exogenous Urokinase Inhibits Proteasomal Degradation of Its Cognate Urokinase Plasminogen Activator Receptor"],"prefix":"10.3389","volume":"13","author":[{"given":"Ran","family":"Zhu","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ting-Wei","family":"Liu","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Fan","family":"Liu","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1965","published-online":{"date-parts":[[2022,8,12]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"1251","DOI":"10.1038\/aps.2013.92","article-title":"Chemokines and Atherosclerosis: Focus on the CX3CL1\/CX3CR1 Pathway","volume":"34","author":"Apostolakis","year":"2013","journal-title":"Acta Pharmacol. 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