{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,3]],"date-time":"2026-06-03T00:25:50Z","timestamp":1780446350375,"version":"3.54.1"},"reference-count":76,"publisher":"American Physiological Society","issue":"2","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["American Journal of Physiology-Heart and Circulatory Physiology"],"published-print":{"date-parts":[[2003,8]]},"abstract":"<jats:p>Chronic inappropriate (relative to dietary Na<jats:sup>+<\/jats:sup>intake) elevations in circulating aldosterone (ALDO), termed aldosteronism, are associated with remodeling of intramural arteries of the right and left heart. Lesions appear at week 4 of treatment with ALDO and 1% dietary NaCl in uninephrectomized rats (ALDOST) and include invading monocytes, macrophages and lymphocytes with intracellular evidence of oxidative and nitrosative stress, myofibroblasts, and perivascular fibrosis. In this study, we tested the hypothesis that an immunostimulatory state with activated circulating peripheral blood mononuclear cells (PBMCs) precedes this proinflammatory and profibrogenic cardiac phenotype and is initiated by reduction in the cytosolic free Mg<jats:sup>2<\/jats:sup><jats:sup>+<\/jats:sup>concentration ([Mg<jats:sup>2<\/jats:sup><jats:sup>+<\/jats:sup>]<jats:sub>i<\/jats:sub>). At 1 and 4 wk of ALDOST (preclinical and clinical stages, respectively), we monitored serum Mg<jats:sup>2<\/jats:sup><jats:sup>+<\/jats:sup>, PBMC [Mg<jats:sup>2<\/jats:sup><jats:sup>+<\/jats:sup>]<jats:sub>i<\/jats:sub>and cytosolic free [Ca<jats:sup>2<\/jats:sup><jats:sup>+<\/jats:sup>] (via fluorimetry), and expressed genes (via microchip array) as well as markers of oxidative and nitrosative stress in plasma [\u03b1<jats:sub>1<\/jats:sub>-antiproteinase activity (\u03b1<jats:sub>1<\/jats:sub>-AP)] and cardiac tissue (immunohistochemical detection of gp91<jats:sup>phox<\/jats:sup>subunit of NADPH oxidase and 3-nitrotyrosine). Age- and gender-matched unoperated and untreated (UO) rats and uninephrectomized salt-treated (UN) rats served as controls. Serum [Mg<jats:sup>2<\/jats:sup><jats:sup>+<\/jats:sup>] was unchanged by ALDOST. In contrast with UO and UN, [Mg<jats:sup>2<\/jats:sup><jats:sup>+<\/jats:sup>]<jats:sub>i<\/jats:sub>and plasma \u03b1<jats:sub>1<\/jats:sub>-AP were each reduced ( P &lt; 0.05) at weeks 1 and 4. The decline in PBMC [Mg<jats:sup>2<\/jats:sup><jats:sup>+<\/jats:sup>]<jats:sub>i<\/jats:sub>was accompanied by Ca<jats:sup>2<\/jats:sup><jats:sup>+<\/jats:sup>loading. Differential (twofold and higher) expression (up- and downregulation) in PBMC transcriptomes was present at week 1 and progressed at week 4. Involved were genes for the \u03b1<jats:sub>1<\/jats:sub>-isoform of Na<jats:sup>+<\/jats:sup>-K<jats:sup>+<\/jats:sup>-ATPase, the ATP-dependent Ca<jats:sup>2<\/jats:sup><jats:sup>+<\/jats:sup>pump, antioxidant reserves, inducible nitric oxide synthase, and PBMC activation with autoimmune responses. Expression of 3-nitrotyrosine and activation of gp91<jats:sup>phox<\/jats:sup>were seen in inflammatory cells that invaded intramural arteries. Thus early in aldosteronism (preclinical stage), an immunostimulatory state featuring activated circulating PBMCs with reduced ionized [Mg<jats:sup>2<\/jats:sup><jats:sup>+<\/jats:sup>]<jats:sub>i<\/jats:sub>and oxidative and nitrosative stress precedes and may even predispose to coronary vascular lesions that first appear at week 4.<\/jats:p>","DOI":"10.1152\/ajpheart.00113.2003","type":"journal-article","created":{"date-parts":[[2015,3,3]],"date-time":"2015-03-03T20:11:15Z","timestamp":1425413475000},"page":"H813-H821","source":"Crossref","is-referenced-by-count":95,"title":["Aldosteronism: an immunostimulatory state precedes proinflammatory\/fibrogenic cardiac phenotype"],"prefix":"10.1152","volume":"285","author":[{"given":"Ivan C.","family":"Gerling","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yao","family":"Sun","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Robert A.","family":"Ahokas","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Linus A.","family":"Wodi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Syamal K.","family":"Bhattacharya","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kenneth J.","family":"Warrington","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Arnold E.","family":"Postlethwaite","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Karl T.","family":"Weber","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"24","reference":[{"key":"REF1","doi-asserted-by":"publisher","DOI":"10.1161\/01.CIR.96.2.526"},{"key":"REF2","doi-asserted-by":"publisher","DOI":"10.1152\/ajpendo.1985.248.3.E388"},{"key":"REF3","doi-asserted-by":"publisher","DOI":"10.1016\/S0733-8651(05)70043-6"},{"key":"REF4","unstructured":"Battifora HA, McCreary PA, Hahneman BM, Laing GH, and Hass GM.Chronic magnesium deficiency in the rat. Studies of chronic myelogenous leukemia.Arch Pathol86: 610\u2013620, 1968."},{"key":"REF5","doi-asserted-by":"publisher","DOI":"10.1080\/00032717708067830"},{"key":"REF6","doi-asserted-by":"publisher","DOI":"10.1007\/BF02815136"},{"key":"REF7","doi-asserted-by":"crossref","unstructured":"Bois P.Tumour of the thymus in magnesium-deficient rats.Nature204: 1316, 1964.","DOI":"10.1038\/2041316a0"},{"key":"REF8","doi-asserted-by":"publisher","DOI":"10.1042\/bj3030061"},{"key":"REF9","doi-asserted-by":"publisher","DOI":"10.1161\/01.RES.67.6.1355"},{"key":"REF10","unstructured":"Brilla CGand Weber KT.Mineralocorticoid excess, dietary sodium and myocardial fibrosis.J Lab Clin Med120: 893\u2013901, 1992."},{"key":"REF11","unstructured":"Brown KCand Kodadek T.Protein cross-linking mediated by metal ion complexes.Met Ions Biol Syst38: 351\u2013384, 2001."},{"key":"REF12","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.270.28.16974"},{"key":"REF13","unstructured":"Bussi\u00e8re FI, Zimowska W, Gueux E, Rayssiguier Y, and Mazur A.Stress protein expression cDNA array study supports activation of neutrophils during acute magnesium deficiency in rats.Magnes Res15: 37\u201342, 2002."},{"key":"REF14","doi-asserted-by":"publisher","DOI":"10.3109\/08037059209077510"},{"key":"REF15","doi-asserted-by":"publisher","DOI":"10.1016\/S0022-2828(95)90359-3"},{"key":"REF16","doi-asserted-by":"publisher","DOI":"10.1161\/hh1501.094115"},{"key":"REF17","doi-asserted-by":"publisher","DOI":"10.1080\/07315724.1985.10720074"},{"key":"REF18","unstructured":"Chen L, Zang Y, Bai B, Zhu M, Zhao B, Hou J, and Xin W.Electron spin resonance determination and superoxide dismutase activity in polymorphonuclear leukocytes in congestive heart failure.Can J Cardiol8: 756\u2013760, 1992."},{"key":"REF19","doi-asserted-by":"publisher","DOI":"10.1016\/S0014-2999(99)00585-3"},{"key":"REF20","doi-asserted-by":"publisher","DOI":"10.1161\/01.HYP.35.1.113"},{"key":"REF21","doi-asserted-by":"publisher","DOI":"10.1016\/S0002-8703(96)90063-0"},{"key":"REF22","doi-asserted-by":"publisher","DOI":"10.1006\/abbi.1998.0937"},{"key":"REF23","doi-asserted-by":"publisher","DOI":"10.1111\/j.1469-7793.1999.001aa.x"},{"key":"REF24","doi-asserted-by":"publisher","DOI":"10.1161\/01.HYP.23.5.587"},{"key":"REF25","doi-asserted-by":"publisher","DOI":"10.1080\/10715769800300481"},{"key":"REF26","doi-asserted-by":"crossref","unstructured":"Grynkiewicz G, Poenie M, and Tsien RY.A new generation of Ca2+indicators with greatly improved fluorescence properties.J Biol Chem260: 3440\u20133450, 1985.","DOI":"10.1016\/S0021-9258(19)83641-4"},{"key":"REF27","unstructured":"Hall CEand Hall O.Hypertension and hypersalimentation. I. Aldosterone hypertension.Lab Invest14: 285\u2013294, 1965."},{"key":"REF28","doi-asserted-by":"crossref","unstructured":"Hanna Sand MacIntyre I.The influence of aldosterone on magnesium metabolism.Lancet2: 348\u2013350, 1960.","DOI":"10.1016\/S0140-6736(60)91487-2"},{"key":"REF29","doi-asserted-by":"publisher","DOI":"10.1096\/fj.02-0126com"},{"key":"REF30","doi-asserted-by":"publisher","DOI":"10.1210\/jcem-22-12-1187"},{"key":"REF31","unstructured":"Jasmin G.Lymph\u0152d\u00e8me, hyperplasie et tum\u00e8faction du tissu lymphatique chez le rat soumis \u00e0 une di\u00e8te d\u00e8ficiente en magn\u00e8sium.Rev Can Biol22: 383\u2013390, 1963."},{"key":"REF32","doi-asserted-by":"publisher","DOI":"10.1016\/S0735-1097(98)00101-6"},{"key":"REF33","doi-asserted-by":"publisher","DOI":"10.1161\/atvb.21.8.1259"},{"key":"REF34","doi-asserted-by":"publisher","DOI":"10.1161\/res.89.4.292"},{"key":"REF35","doi-asserted-by":"publisher","DOI":"10.1080\/07315724.1982.10719002"},{"key":"REF36","doi-asserted-by":"publisher","DOI":"10.1016\/0002-9343(55)90164-9"},{"key":"atypb1","doi-asserted-by":"publisher","DOI":"10.1152\/ajpcell.1996.271.1.C385"},{"key":"REF38","doi-asserted-by":"publisher","DOI":"10.1016\/S0024-3205(98)00455-X"},{"key":"REF39","unstructured":"Martinez DV, Rocha R, Matsumura M, Oestreicher E, Ochoa-Maya M, Roubsanthisuk W, Williams GH, and Adler GK.Cardiac damage prevention by eplerenone: comparison with low sodium diet or potassium loading.Hypertension39: 614\u2013618, 2002."},{"key":"REF40","doi-asserted-by":"crossref","unstructured":"McCreary PA, Battifora HA, Hahneman BM, Laing GH, and Hass GM.Leukocytosis, bone marrow hyperplasia and leukemia in chronic magnesium deficiency in the rat.Blood29: 683\u2013690, 1967.","DOI":"10.1182\/blood.V29.4.683.683"},{"key":"REF41","doi-asserted-by":"publisher","DOI":"10.3181\/00379727-121-30986"},{"key":"REF42","doi-asserted-by":"publisher","DOI":"10.1172\/JCI200114604"},{"key":"REF43","unstructured":"Milne MD, Muehrcke RC, and Aird I.Primary aldosteronism.QJM26: 317\u2013335, 1957."},{"key":"REF44","doi-asserted-by":"publisher","DOI":"10.1016\/S0002-9149(97)89206-5"},{"key":"REF45","doi-asserted-by":"publisher","DOI":"10.1016\/S0008-6363(95)00239-1"},{"key":"REF46","doi-asserted-by":"publisher","DOI":"10.1016\/S0022-510X(97)00157-3"},{"key":"REF47","doi-asserted-by":"publisher","DOI":"10.1016\/S0925-4439(01)00089-8"},{"key":"REF48","doi-asserted-by":"publisher","DOI":"10.1146\/annurev.physiol.62.1.111"},{"key":"REF49","doi-asserted-by":"crossref","unstructured":"Raju B, Murphy E, Levy LA, Hall RD, and London RE.A fluorescent indicator for measuring cytosolic free magnesium.Am J Physiol Cell Physiol256: C540\u2013C548, 1989.","DOI":"10.1152\/ajpcell.1989.256.3.C540"},{"key":"REF50","unstructured":"Rijkers GT, Henriquez N, and Griffioen AW.Intracellular magnesium movements and lymphocyte activation.Magnes Res6: 205\u2013213, 1993."},{"key":"REF51","doi-asserted-by":"publisher","DOI":"10.1111\/j.1469-7793.2000.00037.x"},{"key":"REF52","doi-asserted-by":"publisher","DOI":"10.1161\/01.HYP.24.1.30"},{"key":"REF53","doi-asserted-by":"publisher","DOI":"10.1210\/endo.141.10.7711"},{"key":"REF54","doi-asserted-by":"publisher","DOI":"10.1006\/bbrc.2001.5328"},{"key":"REF55","doi-asserted-by":"publisher","DOI":"10.1016\/0003-9861(92)90086-C"},{"key":"REF56","doi-asserted-by":"publisher","DOI":"10.2741\/A546"},{"key":"REF57","doi-asserted-by":"publisher","DOI":"10.1097\/00004872-199510000-00013"},{"key":"REF58","unstructured":"Ryan MFand Ryan MP.Lymphocyte electrolyte alterations during magnesium deficiency in the rat.Ir J Med Sci148: 108\u2013109, 1979."},{"key":"REF59","doi-asserted-by":"publisher","DOI":"10.1016\/S0005-2736(97)00095-3"},{"key":"REF60","doi-asserted-by":"publisher","DOI":"10.1161\/01.RES.0000045655.34731.B6"},{"key":"REF61","doi-asserted-by":"crossref","unstructured":"Simchowitz L, Foy MA, and Cragoe EJ Jr.A role for Na+\/Ca2+exchange in the generation of superoxide radicals by human neutrophils.J Biol Chem265: 13449\u201313456, 1990.","DOI":"10.1016\/S0021-9258(18)77368-7"},{"key":"REF62","doi-asserted-by":"publisher","DOI":"10.1007\/978-1-4684-4472-8_22"},{"key":"REF63","doi-asserted-by":"publisher","DOI":"10.1016\/S0008-6363(97)00097-7"},{"key":"REF64","unstructured":"Sun Yand Weber KT.Angiotensin II and aldosterone receptor binding in rat heart and kidney: response to chronic angiotensin II or aldosterone administration.J Lab Clin Med122: 404\u2013411, 1993."},{"key":"REF65","doi-asserted-by":"publisher","DOI":"10.1016\/S0002-9440(10)64454-9"},{"key":"REF66","doi-asserted-by":"publisher","DOI":"10.1161\/01.HYP.35.5.1078"},{"key":"REF67","doi-asserted-by":"publisher","DOI":"10.1016\/S0735-1097(96)00268-9"},{"key":"REF68","doi-asserted-by":"publisher","DOI":"10.1016\/0735-1097(95)00589-7"},{"key":"REF69","doi-asserted-by":"publisher","DOI":"10.1161\/01.CIR.104.2.134"},{"key":"REF70","doi-asserted-by":"publisher","DOI":"10.1161\/01.RES.74.5.1009"},{"key":"REF71","doi-asserted-by":"publisher","DOI":"10.1007\/BF01457391"},{"key":"REF72","doi-asserted-by":"publisher","DOI":"10.1016\/0143-4160(90)90010-R"},{"key":"REF73","doi-asserted-by":"publisher","DOI":"10.1002\/(SICI)1097-4644(19981201)71:3<441::AID-JCB12>3.0.CO;2-O"},{"key":"REF74","doi-asserted-by":"publisher","DOI":"10.1016\/S0008-6363(02)00238-9"},{"key":"REF75","doi-asserted-by":"publisher","DOI":"10.1152\/ajpendo.1995.269.4.E657"},{"key":"REF76","doi-asserted-by":"publisher","DOI":"10.1016\/S0952-7915(02)00367-9"}],"container-title":["American Journal of Physiology-Heart and Circulatory Physiology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.physiology.org\/doi\/pdf\/10.1152\/ajpheart.00113.2003","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,5,1]],"date-time":"2022-05-01T09:15:40Z","timestamp":1651396540000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.physiology.org\/doi\/10.1152\/ajpheart.00113.2003"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2003,8]]},"references-count":76,"journal-issue":{"issue":"2","published-print":{"date-parts":[[2003,8]]}},"alternative-id":["10.1152\/ajpheart.00113.2003"],"URL":"https:\/\/doi.org\/10.1152\/ajpheart.00113.2003","relation":{},"ISSN":["0363-6135","1522-1539"],"issn-type":[{"value":"0363-6135","type":"print"},{"value":"1522-1539","type":"electronic"}],"subject":[],"published":{"date-parts":[[2003,8]]}}}