{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,25]],"date-time":"2026-03-25T20:37:08Z","timestamp":1774471028021,"version":"3.50.1"},"reference-count":44,"publisher":"MDPI AG","issue":"3","license":[{"start":{"date-parts":[[2020,3,6]],"date-time":"2020-03-06T00:00:00Z","timestamp":1583452800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Ministry of Economy and Competitiveness,Spain.","award":["SAF2013-49088-R and SAF2016-79151-R."],"award-info":[{"award-number":["SAF2013-49088-R and SAF2016-79151-R."]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cells"],"abstract":"<jats:p>Oxidative stress is a main molecular mechanism that underlies cardiovascular diseases. A close relationship between reactive oxygen species (ROS) derived from NADPH oxidase (NOX) activity and the prostaglandin (PG) biosynthesis pathway has been described. However, little information is available about the interaction between NOX5 homolog-derived ROS and the PG pathway in the cardiovascular context. Our main goal was to characterize NOX5-derived ROS effects in PG homeostasis and their potential relevance in cardiovascular pathologies. For that purpose, two experimental systems were employed: an adenoviral NOX5-\u03b2 overexpression model in immortalized human aortic endothelial cells (TeloHAEC) and a chronic infarction in vivo model developed from a conditional endothelial NOX5 knock-in mouse. NOX5 increased cyclooxygenase-2 isoform (COX-2) expression and prostaglandin E2 (PGE2) production through nuclear factor kappa-light-chain-enhancer of activated B cells (NF-\u03baB) in TeloHAEC. Protein kinase C (PKC) activation and intracellular calcium level (Ca++) mobilization increased ROS production and NOX5 overexpression, which promoted a COX-2\/PGE2 response in vitro. In the chronic infarction model, mice encoding endothelial NOX5 enhanced the cardiac mRNA expression of COX-2 and PGES, suggesting a COX-2\/PGE2 response to NOX5 presence in an ischemic situation. Our data support that NOX5-derived ROS may modulate the COX-2\/PGE2 axis in endothelial cells, which might play a relevant role in the pathophysiology of heart infarction.<\/jats:p>","DOI":"10.3390\/cells9030637","type":"journal-article","created":{"date-parts":[[2020,3,6]],"date-time":"2020-03-06T09:26:41Z","timestamp":1583486801000},"page":"637","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":26,"title":["Induction of Cyclooxygenase-2 by Overexpression of the Human NADPH Oxidase 5 (NOX5) Gene in Aortic Endothelial Cells"],"prefix":"10.3390","volume":"9","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-3075-8520","authenticated-orcid":false,"given":"Javier","family":"Marqu\u00e9s","sequence":"first","affiliation":[{"name":"Department of Biochemistry and Genetics, University of Navarra, 31008 Pamplona, Spain"},{"name":"Navarra Institute for Health Research (IdiSNA), 31008 Pamplona, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9474-8524","authenticated-orcid":false,"given":"Adriana","family":"Cort\u00e9s","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Genetics, University of Navarra, 31008 Pamplona, Spain"},{"name":"Navarra Institute for Health Research (IdiSNA), 31008 Pamplona, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"\u00c1lvaro","family":"Pejenaute","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Genetics, University of Navarra, 31008 Pamplona, Spain"},{"name":"Navarra Institute for Health Research (IdiSNA), 31008 Pamplona, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1517-7859","authenticated-orcid":false,"given":"Eduardo","family":"Ansorena","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Genetics, University of Navarra, 31008 Pamplona, Spain"},{"name":"Navarra Institute for Health Research (IdiSNA), 31008 Pamplona, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Gloria","family":"Abizanda","sequence":"additional","affiliation":[{"name":"Navarra Institute for Health Research (IdiSNA), 31008 Pamplona, Spain"},{"name":"Hematology Service, Cl\u00ednica Universidad de Navarra, University of Navarra, 31008 Pamplona, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6115-8790","authenticated-orcid":false,"given":"Felipe","family":"Pr\u00f3sper","sequence":"additional","affiliation":[{"name":"Navarra Institute for Health Research (IdiSNA), 31008 Pamplona, Spain"},{"name":"Hematology Service, Cl\u00ednica Universidad de Navarra, University of Navarra, 31008 Pamplona, Spain"},{"name":"CIBERONC, 31008 Madrid, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4576-8139","authenticated-orcid":false,"given":"Juan Jos\u00e9","family":"Mart\u00ednez-Irujo","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Genetics, University of Navarra, 31008 Pamplona, Spain"},{"name":"Navarra Institute for Health Research (IdiSNA), 31008 Pamplona, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Carlos de","family":"Miguel","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Genetics, University of Navarra, 31008 Pamplona, Spain"},{"name":"Navarra Institute for Health Research (IdiSNA), 31008 Pamplona, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4616-1523","authenticated-orcid":false,"given":"Guillermo","family":"Zalba","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Genetics, University of Navarra, 31008 Pamplona, Spain"},{"name":"Navarra Institute for Health Research (IdiSNA), 31008 Pamplona, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2020,3,6]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"2061","DOI":"10.1113\/JP270538","article-title":"Ageing, metabolism and cardiovascular disease","volume":"594","author":"Costantino","year":"2016","journal-title":"J. Physiol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"70","DOI":"10.1007\/s11906-011-0238-3","article-title":"The Nox family of NADPH oxidases: Friend or foe of the vascular system?","volume":"14","author":"Takac","year":"2012","journal-title":"Curr. Hypertens. Rep."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"195","DOI":"10.1007\/s10557-007-6027-1","article-title":"Atherosclerosis and oxidant stress: The end of the road for antioxidant vitamin treatment?","volume":"21","author":"Thomsom","year":"2007","journal-title":"Cardiovasc. Drugs Ther."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"5","DOI":"10.1038\/hr.2010.201","article-title":"Reactive oxygen species and vascular biology: Implications in human hypertension","volume":"34","author":"Touyz","year":"2011","journal-title":"Hypertens. Res."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"170","DOI":"10.1038\/s41569-019-0260-8","article-title":"NADPH oxidases and oxidase crosstalk in cardiovascular diseases: Novel therapeutic targets","volume":"17","author":"Zhang","year":"2020","journal-title":"Nat. Rev. Cardiol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"1919","DOI":"10.1152\/ajpheart.00910.2011","article-title":"Expression and functional significance of NADPH oxidase 5 (Nox5) and its splice variants in human blood vessels","volume":"302","author":"Pandey","year":"2012","journal-title":"Am. J. Physiol. Heart Circ. Physiol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"5999","DOI":"10.2174\/1381612821666151029111528","article-title":"Enzymatic regulation and functional relevance of NOX5","volume":"21","author":"Chen","year":"2015","journal-title":"Curr. Pharm. Des."},{"key":"ref_8","doi-asserted-by":"crossref","unstructured":"Chen, F., Yu, Y., Haigh, S., Johnson, J., Lucas, R., Stepp, D.W., and Fulton, D.J. (2014). Regulation of NADPH oxidase 5 by protein kinase C isoforms. PLoS ONE, 9.","DOI":"10.1371\/journal.pone.0088405"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"77","DOI":"10.1016\/j.bcp.2017.03.003","article-title":"Resveratrol inhibits BK-induced COX-2 transcription by supressing acetylation of AP-1 and NF-\u1d0bB in human rheumatoid arthritis synovial fibroblasts","volume":"132","author":"Yang","year":"2017","journal-title":"Biochem. Pharmacol."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"890","DOI":"10.1016\/S0891-5849(02)00775-X","article-title":"Nuclear factor-kappaB mediates over-expression of cyclooxygenase-2 during activation of RAW 264.7 macrophages in selenium deficiency","volume":"32","author":"Lu","year":"2002","journal-title":"Free Radic. Biol. Med."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"240","DOI":"10.1152\/ajpcell.00597.2008","article-title":"Titanium particles stimulate COX-2 expression in synovial fibroblasts through an oxidative stress-induced, calpain-dependent, NF-kappaB pathway","volume":"297","author":"Wei","year":"2009","journal-title":"Am. J. Physiol. Cell Physiol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"1009","DOI":"10.1016\/0002-9343(81)90335-1","article-title":"Prostaglandins and ischemic heart disease","volume":"71","author":"Hirsh","year":"1981","journal-title":"Am. J. Med."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"55","DOI":"10.1016\/j.plefa.2013.04.004","article-title":"The role of prostaglandin E2 in human vascular inflammation","volume":"89","author":"Gomez","year":"2013","journal-title":"Prostaglandins Leukot. Essent. Fatty Acids"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"240","DOI":"10.1016\/j.taap.2014.06.012","article-title":"Eupafolin inhibits PGE2 production and COX2 expression in LPS-stimulated human dermal fibroblasts by blocking JNK\/AP-1 and Nox2\/p47(phox) pathway","volume":"279","author":"Tsai","year":"2014","journal-title":"Toxicol. Appl. Pharmacol."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"2039","DOI":"10.1007\/s00204-014-1359-7","article-title":"Endosulfan induces COX-2 expression via NADPH oxidase and the ROS, MAPK, and Akt pathways","volume":"89","author":"Kim","year":"2015","journal-title":"Arch. Toxicol."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"126","DOI":"10.1016\/j.fct.2013.11.035","article-title":"Genipin induces cyclooxygenase-2 expression via NADPH oxidase, MAPKs, AP-1, and NF-\u1d0bB in RAW 264.7 cells","volume":"64","author":"Khanal","year":"2014","journal-title":"Food Chem. Toxicol."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"978","DOI":"10.1124\/mol.112.083287","article-title":"NADPH oxidase NOX5-S and nuclear factor \u1d0bB1 mediate acid-induced microsomal prostaglandin E synthase-1 expression in Barrett\u2019s esophageal adenocarcinoma cells","volume":"83","author":"Zhou","year":"2013","journal-title":"Mol. Pharmacol."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"95","DOI":"10.1016\/j.bcp.2010.03.009","article-title":"Sphingosylphosphorylcholine down-regulates filaggrin gene transcription through NOX5-based NADPH oxidase and cyclooxygenase-2 in human keratinocytes","volume":"80","author":"Choi","year":"2010","journal-title":"Biochem. Pharmacol."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"15","DOI":"10.1016\/j.freeradbiomed.2018.07.013","article-title":"NADPH oxidase 5 promotes proliferation and fibrosis in human hepatic stellate cells","volume":"126","author":"Andueza","year":"2018","journal-title":"Free Radic. Biol. Med."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"51","DOI":"10.1002\/term.7","article-title":"Multipotent adult progenitor cell transplantation increases vascularity and improves left ventricular function after myocardial infarction","volume":"1","author":"Pelacho","year":"2007","journal-title":"J. Tissue Eng. Regen. Med."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"192","DOI":"10.1253\/circj.66.192","article-title":"Transmitral inflow pattern assessed by Doppler echocardiography in angiotensin II type 1A receptor knock out mice with myocardial infarction","volume":"66","author":"Nakamura","year":"2002","journal-title":"Circ. J."},{"key":"ref_22","doi-asserted-by":"crossref","unstructured":"Benavides-Vallve, C., Corbacho, D., Iglesias-Garcia, O., Pelacho, B., Albiasu, E., Casta\u00f1o, S., Mu\u00f1oz-Barrutia, A., Prosper, F., and Ortiz-de-Solozarno, C. (2012). New strategies for echocardiographic evaluation of left ventricular function in a mouse model of long-term myocardial infarction. PLoS ONE, 7.","DOI":"10.1371\/journal.pone.0041691"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"60","DOI":"10.1016\/j.freeradbiomed.2019.12.038","article-title":"Isoform-selective NADPH oxidase inhibitor panel for pharmacological target validation","volume":"148","author":"Dao","year":"2019","journal-title":"Free Radic. Biol. Med."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"1363","DOI":"10.1161\/CIRCRESAHA.109.216036","article-title":"Nicotinamide adenine dinucleotide phosphate reduced oxidase 5 (Nox5) regulation by angiotensin II and endothelin-1 is mediated via calcium\/calmodulin-dependent, rac-1-independent pathways in human endothelial cells","volume":"106","author":"Montezano","year":"2010","journal-title":"Circ. Res."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"1134","DOI":"10.2174\/1381612820666141014142557","article-title":"Reactive oxygen species in pathogenesis of atherosclerosis","volume":"21","author":"Goncharov","year":"2015","journal-title":"Curr. Pharm. Des."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"6819281","DOI":"10.1155\/2017\/6819281","article-title":"Cardioprotective effect of resveratrol in a postinfarction heart failure model","volume":"2017","author":"Riba","year":"2017","journal-title":"Oxid. Med. Cell Longev."},{"key":"ref_27","doi-asserted-by":"crossref","unstructured":"Ren, J., Su, D., Li, L., Cai, H., Zhang, M., Zhai, J., Li, M., Wu, X., and Hu, K. (2019). Anti-inflammatory effects of Aureusidin in LPS-stimulated RAW264.7 macrophages via supressing NF-\u1d0bB and activating ROS- and MAPKs-dependent Nrf2\/HO-1 signaling pathways. Toxicol. Appl. Pharmacol., 387\u2013114846.","DOI":"10.1016\/j.taap.2019.114846"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"113","DOI":"10.1016\/j.biocel.2017.05.015","article-title":"Resveratrol inhibits urban particulate matter-induced COX-2\/PGE2 release in human fibroblast-like synoviocytes via the inhibition of activation of NADPH oxidase\/ROS\/NF-\u1d0bB","volume":"88","author":"Tsai","year":"2017","journal-title":"Int. J. Biochem. Cell Biol."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"81","DOI":"10.1016\/j.etap.2018.04.012","article-title":"18\u03b2-Glycyrrhetinic acid mitigates radiation-induced skin damage via NADPH oxidase\/ROS\/p38MAPK and NF-\u1d0bB pathways","volume":"60","author":"Su","year":"2018","journal-title":"Environ. Toxicol. Pharmacol."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"1159","DOI":"10.1016\/j.biochi.2007.05.004","article-title":"NOX5 is expressed at the plasma membrane and generates superoxide in response to protein kinase C activation","volume":"89","author":"Serrander","year":"2007","journal-title":"Biochimie"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"344","DOI":"10.1080\/10641963.2017.1377218","article-title":"Hypertension regulating angiotensin peptides in the pathobiology of cardiovascular disease","volume":"40","author":"Hussain","year":"2018","journal-title":"Clin. Exp. Hypertens."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"431","DOI":"10.1007\/s11906-014-0431-2","article-title":"Angiotensin II and vascular injury","volume":"16","author":"Montezano","year":"2014","journal-title":"Curr. Hypertens. Rep."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"139","DOI":"10.1016\/j.bcp.2017.09.008","article-title":"Free-fatty acid receptor-4 (FFA4) modulates ROS generation and COX-2 expression via the C-terminal \u03b2-arrestin phosphosensor in Raw 264.7 macrophages","volume":"146","author":"Cheshmehkani","year":"2017","journal-title":"Biochem. Pharmacol."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"1582","DOI":"10.1152\/ajpheart.00924.2013","article-title":"Pioglitazone reduces angiotensin II-induced COX-2 expression through inhibition of ROS production and ET-1 transcription in vascular cells from spontaneously hypertensive rats","volume":"306","author":"Palacios","year":"2014","journal-title":"Am. J. Physiol. Heart Circ. Physiol."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"835","DOI":"10.3892\/etm.2017.4062","article-title":"Atorvastatin attenuates plaque vulnerability by downregulation of EMMPRIN expression via COX-2\/PGE2 pathway","volume":"13","author":"Liang","year":"2017","journal-title":"Exp. Ther. Med."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"354","DOI":"10.1016\/j.freeradbiomed.2018.09.046","article-title":"Up-regulation of COX-2 and mPGES-1 by 27-hydroxycholesterol and 4-hydroxynonenal: A crucial role in atherosclerotic plaque instability","volume":"129","author":"Gargiulo","year":"2018","journal-title":"Free Radic. Biol. Med."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"1803","DOI":"10.1016\/j.jacc.2008.07.063","article-title":"Calcium-dependent NOX5 nicotinamide adenine dinucleotide phosphate oxidase contributes to vascular oxidative stress in human coronary artery disease","volume":"52","author":"Guzik","year":"2008","journal-title":"J. Am. Coll. Cardiol."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"76","DOI":"10.1016\/j.freeradbiomed.2018.01.024","article-title":"ROS and redox signaling in myocardial ischemia-reperfusion injury and cardioprotection","volume":"117","author":"Cardenas","year":"2018","journal-title":"Free Radic. Biol. Med."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"2222","DOI":"10.1016\/j.ajpath.2012.02.018","article-title":"NOX5 expression is increased in intramyocardial blood vessels and cardiomyocytes after acute myocardial infarction in humans","volume":"180","author":"Hahn","year":"2012","journal-title":"Am. J. Pathol."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"1595","DOI":"10.2174\/092986707780830998","article-title":"COX-2 expression in atherosclerosis: The good, the bad or the ugly?","volume":"14","author":"Cuccurullo","year":"2007","journal-title":"Curr. Med. Chem."},{"key":"ref_41","first-page":"2924731","article-title":"A variant in COX-2 gene is associated with left main coronary artery disease and clinical outcomes of coronary artery bypass grafting","volume":"2017","author":"Liu","year":"2017","journal-title":"Biomed. Res. Int."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"2242","DOI":"10.1093\/eurheartj\/ehu168","article-title":"Association of cyclooxygenase-2 genetic variant with cardiovascular disease","volume":"35","author":"Ross","year":"2014","journal-title":"Eur. Heart J."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"32","DOI":"10.1007\/s00395-019-0741-2","article-title":"Inducible cardiac-specific overexpression of cyclooxygenase-2 (COX-2) confers resistance to ischemia\/reperfusion injury","volume":"114","author":"Guo","year":"2019","journal-title":"Basic Res. Cardiol."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"957","DOI":"10.1111\/bcp.13048","article-title":"Cardiovascular effects of cyclooxygenase-2 inhibitors: A mechanistic and clinical perspective","volume":"84","author":"Patrono","year":"2016","journal-title":"Br. J. Clin. Pharmacol."}],"container-title":["Cells"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2073-4409\/9\/3\/637\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T09:04:45Z","timestamp":1760173485000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2073-4409\/9\/3\/637"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2020,3,6]]},"references-count":44,"journal-issue":{"issue":"3","published-online":{"date-parts":[[2020,3]]}},"alternative-id":["cells9030637"],"URL":"https:\/\/doi.org\/10.3390\/cells9030637","relation":{},"ISSN":["2073-4409"],"issn-type":[{"value":"2073-4409","type":"electronic"}],"subject":[],"published":{"date-parts":[[2020,3,6]]}}}