{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,4]],"date-time":"2026-10-04T11:32:54Z","timestamp":1791113574765,"version":"4.1.0"},"reference-count":32,"publisher":"The Endocrine Society","issue":"3","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2008,3,1]]},"abstract":"<jats:p>Currently, aldosterone is believed to be involved in the development of cardiovascular injury as a potential cardiovascular risk hormone. However, its exact cellular mechanisms remain obscure. This study was undertaken to examine the effect of aldosterone on superoxide production in cultured rat aortic endothelial cells with possible involvement of the small GTP-binding (G) protein Rac1. The aldosterone levels showed a time-dependent (6\u201324 h) and dose-dependent (10\u22128 to 10\u22126m) increase in superoxide generation, whose effect was abolished by mineralocorticoid receptor antagonist (eplerenone), Src inhibitor (PP2), and reduced nicotinamide adenine dinucleotide phosphate [NAD(P)H] oxidase inhibitor (apocynin). Aldosterone activated NADP(H) oxidase and Rac1, whose effects were abolished by eplerenone. The aldosterone-induced superoxide generation was abolished either by nonselective small G protein inhibitor (Clostridium difficile toxin A) or dominant-negative Rac1. Dominant-negative Rac1 also inhibited aldosterone-induced ACE gene expression. Thus, the present study is the first to demonstrate that aldosterone induces superoxide generation via mineralocorticoid receptor-mediated activation of NAD(P)H-oxidase and Rac1 in endothelial cells, thereby contributing to the development of aldosterone-induced vascular injury.<\/jats:p>","DOI":"10.1210\/en.2007-0864","type":"journal-article","created":{"date-parts":[[2007,12,14]],"date-time":"2007-12-14T01:45:14Z","timestamp":1197596714000},"page":"1009-1014","source":"Crossref","is-referenced-by-count":114,"title":["Aldosterone Induces Superoxide Generation via Rac1 Activation in Endothelial Cells"],"prefix":"10.1210","volume":"149","author":[{"given":"Fumiko","family":"Iwashima","sequence":"first","affiliation":[{"name":"Department of Clinical and Molecular Endocrinology, Tokyo Medical and Dental University Graduate School, Tokyo 113-8519, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Takanobu","family":"Yoshimoto","sequence":"first","affiliation":[{"name":"Department of Clinical and Molecular Endocrinology, Tokyo Medical and Dental University Graduate School, Tokyo 113-8519, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Isao","family":"Minami","sequence":"first","affiliation":[{"name":"Department of Clinical and Molecular Endocrinology, Tokyo Medical and Dental University Graduate School, Tokyo 113-8519, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maya","family":"Sakurada","sequence":"first","affiliation":[{"name":"Department of Clinical and Molecular Endocrinology, Tokyo Medical and Dental University Graduate School, Tokyo 113-8519, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuki","family":"Hirono","sequence":"first","affiliation":[{"name":"Department of Clinical and Molecular Endocrinology, Tokyo Medical and Dental University Graduate School, Tokyo 113-8519, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yukio","family":"Hirata","sequence":"first","affiliation":[{"name":"Department of Clinical and Molecular Endocrinology, Tokyo Medical and Dental University Graduate School, Tokyo 113-8519, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"80","published-online":{"date-parts":[[2007,12,13]]},"reference":[{"key":"2020071612243147800_R1","doi-asserted-by":"crossref","first-page":"263","DOI":"10.1016\/j.mce.2003.10.054","article-title":"Aldosterone, mineralocorticoid receptors and vascular inflammation.","volume":"217","author":"Funder","year":"2004","journal-title":"Mol Cell Endocrinol"},{"key":"2020071612243147800_R2","doi-asserted-by":"crossref","first-page":"89","DOI":"10.1111\/j.1749-6632.2002.tb04415.x","article-title":"The pathophysiology of aldosterone in the cardiovascular system.","volume":"970","author":"Rocha","year":"2002","journal-title":"Ann NY Acad Sci"},{"key":"2020071612243147800_R3","doi-asserted-by":"crossref","first-page":"312","DOI":"10.1161\/01.HYP.0000201443.63240.a7","article-title":"Effects of aldosterone on the vasculature.","volume":"47","author":"Schiffrin","year":"2006","journal-title":"Hypertension"},{"key":"2020071612243147800_R4","doi-asserted-by":"crossref","first-page":"1831","DOI":"10.1161\/01.CIR.0000091405.00772.6E","article-title":"Effects of eplerenone, enalapril, and eplerenone\/enalapril in patients with essential hypertension and left ventricular hypertrophy: the 4E-left ventricular hypertrophy study.","volume":"108","author":"Pitt","year":"2003","journal-title":"Circulation"},{"key":"2020071612243147800_R5","doi-asserted-by":"crossref","first-page":"1309","DOI":"10.1056\/NEJMoa030207","article-title":"Eplerenone, a selective aldosterone blocker, in patients with left ventricular dysfunction after myocardial infarction.","volume":"348","author":"Pitt","year":"2003","journal-title":"N Engl J Med"},{"key":"2020071612243147800_R6","doi-asserted-by":"crossref","first-page":"709","DOI":"10.1056\/NEJM199909023411001","article-title":"The effect of spironolactone on morbidity and mortality in patients with severe heart failure. Randomized Aldactone Evaluation Study Investigators.","volume":"341","author":"Pitt","year":"1999","journal-title":"N Engl J Med"},{"key":"2020071612243147800_R7","doi-asserted-by":"crossref","first-page":"85","DOI":"10.1023\/B:MCBI.0000044378.09409.b5","article-title":"Reactive oxygen species as mediators of angiogenesis signaling: role of NAD(P)H oxidase.","volume":"264","author":"Ushio-Fukai","year":"2004","journal-title":"Mol Cell Biochem"},{"key":"2020071612243147800_R8","doi-asserted-by":"crossref","first-page":"R277","DOI":"10.1152\/ajpregu.00758.2002","article-title":"Vascular NAD(P)H oxidases: specific features, expression, and regulation","volume":"285","author":"Lassegue","year":"2003","journal-title":"Am J Physiol Regul Integr Comp Physiol"},{"key":"2020071612243147800_R9","doi-asserted-by":"crossref","first-page":"494","DOI":"10.1161\/01.RES.86.5.494","article-title":"NAD(P)H oxidase: role in cardiovascular biology and disease.","volume":"86","author":"Griendling","year":"2000","journal-title":"Circ Res"},{"key":"2020071612243147800_R10","doi-asserted-by":"crossref","first-page":"1107","DOI":"10.1161\/hy1101.093423","article-title":"NADH\/NADPH oxidase and enhanced superoxide production in the mineralocorticoid hypertensive rat.","volume":"38","author":"Beswick","year":"2001","journal-title":"Hypertension"},{"key":"2020071612243147800_R11","doi-asserted-by":"crossref","first-page":"1688","DOI":"10.1210\/en.2006-1157","article-title":"Angiotensin II receptor type 1-mediated vascular oxidative stress and proinflammatory gene expression in aldosterone-induced hypertension: the possible role of local renin-angiotensin system.","volume":"148","author":"Hirono","year":"2007","journal-title":"Endocrinology"},{"key":"2020071612243147800_R12","doi-asserted-by":"crossref","first-page":"229","DOI":"10.1016\/j.mce.2003.10.047","article-title":"Aldosterone target organ protection by eplerenone.","volume":"217","author":"Rudolph","year":"2004","journal-title":"Mol Cell Endocrinol"},{"key":"2020071612243147800_R13","doi-asserted-by":"crossref","first-page":"1773","DOI":"10.1016\/S0002-9440(10)64454-9","article-title":"Aldosterone-induced inflammation in the rat heart: role of oxidative stress.","volume":"161","author":"Sun","year":"2002","journal-title":"Am J Pathol"},{"key":"2020071612243147800_R14","doi-asserted-by":"crossref","first-page":"453","DOI":"10.1161\/01.RES.0000204727.46710.5e","article-title":"Regulation of NADPH oxidases: the role of Rac proteins.","volume":"98","author":"Hordijk","year":"2006","journal-title":"Circ Res"},{"key":"2020071612243147800_R15","doi-asserted-by":"crossref","first-page":"III27","DOI":"10.1161\/01.CIR.0000131515.03336.f8","article-title":"Role of endothelial dysfunction in atherosclerosis.","volume":"109","author":"Davignon","year":"2004","journal-title":"Circulation"},{"key":"2020071612243147800_R16","doi-asserted-by":"crossref","first-page":"115","DOI":"10.1056\/NEJM199901143400207","article-title":"Atherosclerosis: an inflammatory disease.","volume":"340","author":"Ross","year":"1999","journal-title":"N Engl J Med"},{"key":"2020071612243147800_R17","doi-asserted-by":"crossref","first-page":"163","DOI":"10.1016\/j.bbrc.2005.08.056","article-title":"Aldosterone increases osteopontin gene expression in rat endothelial cells.","volume":"336","author":"Sugiyama","year":"2005","journal-title":"Biochem Biophys Res Commun"},{"key":"2020071612243147800_R18","doi-asserted-by":"crossref","first-page":"3900","DOI":"10.1210\/en.2004-1674","article-title":"Aldosterone induces angiotensin converting enzyme gene expression via a JAK2-dependent pathway in rat endothelial cells.","volume":"146","author":"Sugiyama","year":"2005","journal-title":"Endocrinology"},{"key":"2020071612243147800_R19","doi-asserted-by":"crossref","first-page":"224","DOI":"10.1007\/BF03402119","article-title":"Efficient generation of recombinant adenoviral vectors by Cre-lox recombination in vitro.","volume":"5","author":"Aoki","year":"1999","journal-title":"Mol Med"},{"key":"2020071612243147800_R20","first-page":"94","article-title":"Isolation of rat aortic endothelial cells by primary explant techniques and their phenotypic modulation by defined substrata.","volume":"57","author":"McGuire","year":"1987","journal-title":"Lab Invest"},{"key":"2020071612243147800_R21","doi-asserted-by":"crossref","first-page":"1116","DOI":"10.1016\/S0891-5849(02)00789-X","article-title":"The vascular NADPH oxidase subunit p47phox is involved in redox-mediated gene expression.","volume":"32","author":"Brandes","year":"2002","journal-title":"Free Radic Biol Med"},{"key":"2020071612243147800_R22","doi-asserted-by":"crossref","first-page":"3331","DOI":"10.1210\/en.2003-1583","article-title":"Antioxidant effect of adrenomedullin on angiotensin II-induced reactive oxygen species generation in vascular smooth muscle cells.","volume":"145","author":"Yoshimoto","year":"2004","journal-title":"Endocrinology"},{"key":"2020071612243147800_R23","doi-asserted-by":"crossref","first-page":"165","DOI":"10.1291\/hypres.28.165","article-title":"Adrenomedullin inhibits angiotensin II-induced oxidative stress and gene expression in rat endothelial cells.","volume":"28","author":"Yoshimoto","year":"2005","journal-title":"Hypertens Res"},{"key":"2020071612243147800_R24","doi-asserted-by":"crossref","first-page":"13198","DOI":"10.1074\/jbc.274.19.13198","article-title":"Characterization of rac and cdc42 activation in chemoattractant-stimulated human neutrophils using a novel assay for active GTPases.","volume":"274","author":"Benard","year":"1999","journal-title":"J Biol Chem"},{"key":"2020071612243147800_R25","doi-asserted-by":"crossref","first-page":"53","DOI":"10.1016\/0092-8674(95)90370-4","article-title":"Rho, rac, and cdc42 GTPases regulate the assembly of multimolecular focal complexes associated with actin stress fibers, lamellipodia, and filopodia.","volume":"81","author":"Nobes","year":"1995","journal-title":"Cell"},{"key":"2020071612243147800_R26","doi-asserted-by":"crossref","first-page":"401","DOI":"10.1016\/0092-8674(92)90164-8","article-title":"The small GTP-binding protein rac regulates growth factor-induced membrane ruffling.","volume":"70","author":"Ridley","year":"1992","journal-title":"Cell"},{"key":"2020071612243147800_R27","doi-asserted-by":"crossref","first-page":"773","DOI":"10.1161\/01.HYP.0000154365.30593.d3","article-title":"Aldosterone activates vascular p38MAP kinase and NADPH oxidase via c-Src.","volume":"45","author":"Callera","year":"2005","journal-title":"Hypertension"},{"key":"2020071612243147800_R28","doi-asserted-by":"crossref","first-page":"165","DOI":"10.1161\/01.HYP.0000226054.53527.bb","article-title":"Molecular mechanism of the inhibitory effect of aldosterone on endothelial NO synthase activity.","volume":"48","author":"Nagata","year":"2006","journal-title":"Hypertension"},{"key":"2020071612243147800_R29","doi-asserted-by":"crossref","first-page":"342","DOI":"10.1006\/abbi.2001.2642","article-title":"The neutrophil NADPH oxidase.","volume":"397","author":"Babior","year":"2002","journal-title":"Arch Biochem Biophys"},{"key":"2020071612243147800_R30","doi-asserted-by":"crossref","first-page":"406","DOI":"10.1161\/01.RES.0000033523.08033.16","article-title":"Angiotensin II stimulation of NAD(P)H oxidase activity: upstream mediators.","volume":"91","author":"Seshiah","year":"2002","journal-title":"Circ Res"},{"key":"2020071612243147800_R31","doi-asserted-by":"crossref","first-page":"189","DOI":"10.1038\/nm1545","article-title":"Aldosterone impairs vascular reactivity by decreasing glucose-6-phosphate dehydrogenase activity.","volume":"13","author":"Leopold","year":"2007","journal-title":"Nat Med"},{"key":"2020071612243147800_R32","doi-asserted-by":"crossref","first-page":"121","DOI":"10.1080\/1071576021000040655","article-title":"The role of tetrahydrobiopterin in superoxide generation from eNOS: enzymology and physiological implications.","volume":"37","author":"Vasquez-Vivar","year":"2003","journal-title":"Free Radic Res"}],"container-title":["Endocrinology"],"original-title":[],"language":"en","link":[{"URL":"http:\/\/academic.oup.com\/endo\/article-pdf\/149\/3\/1009\/8997672\/endo1009.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"http:\/\/academic.oup.com\/endo\/article-pdf\/149\/3\/1009\/8997672\/endo1009.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2020,7,16]],"date-time":"2020-07-16T20:09:09Z","timestamp":1594930149000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/endo\/article\/149\/3\/1009\/2455008"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2007,12,13]]},"references-count":32,"journal-issue":{"issue":"3","published-print":{"date-parts":[[2008,3,1]]}},"URL":"https:\/\/doi.org\/10.1210\/en.2007-0864","relation":{},"ISSN":["0013-7227","1945-7170"],"issn-type":[{"value":"0013-7227","type":"print"},{"value":"1945-7170","type":"electronic"}],"subject":[],"published":{"date-parts":[[2007,12,13]]}}}