{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,3]],"date-time":"2026-08-03T16:58:01Z","timestamp":1785776281885,"version":"3.56.0"},"reference-count":43,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"8","content-domain":{"domain":["www.ahajournals.org"],"crossmark-restriction":true},"short-container-title":["Circulation"],"published-print":{"date-parts":[[2012,8,21]]},"abstract":"<jats:sec>\n                    <jats:title>Background\u2014<\/jats:title>\n                    <jats:p>\n                      Pulmonary arterial hypertension (PAH) is characterized, in part, by decreased endothelial nitric oxide (NO\n                      <jats:sup>\u00b7<\/jats:sup>\n                      ) production and elevated levels of endothelin-1. Endothelin-1 is known to stimulate endothelial nitric oxide synthase (eNOS) via the endothelin-B receptor (ET\n                      <jats:sub>B<\/jats:sub>\n                      ), suggesting that this signaling pathway is perturbed in PAH. Endothelin-1 also stimulates adrenal aldosterone synthesis; in systemic blood vessels, hyperaldosteronism induces vascular dysfunction by increasing endothelial reactive oxygen species generation and decreasing NO\n                      <jats:sup>\u00b7<\/jats:sup>\n                      levels. We hypothesized that aldosterone modulates PAH by disrupting ET\n                      <jats:sub>B<\/jats:sub>\n                      -eNOS signaling through a mechanism involving increased pulmonary endothelial oxidant stress.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods and Results\u2014<\/jats:title>\n                    <jats:p>\n                      In rats with PAH, elevated endothelin-1 levels were associated with elevated aldosterone levels in plasma and lung tissue and decreased lung NO\n                      <jats:sup>\u00b7<\/jats:sup>\n                      metabolites in the absence of left-sided heart failure. In human pulmonary artery endothelial cells, endothelin-1 increased aldosterone levels via peroxisome proliferator-activated receptor gamma coactivator-1\u03b1\/steroidogenesis factor-1\u2013dependent upregulation of aldosterone synthase. Aldosterone also increased reactive oxygen species production, which oxidatively modified cysteinyl thiols in the eNOS-activating region of ET\n                      <jats:sub>B<\/jats:sub>\n                      to decrease endothelin-1\u2013stimulated eNOS activity. Substitution of ET\n                      <jats:sub>B<\/jats:sub>\n                      -Cys405 with alanine improved ET\n                      <jats:sub>B<\/jats:sub>\n                      -dependent NO\n                      <jats:sup>\u00b7<\/jats:sup>\n                      synthesis under conditions of oxidant stress, confirming that Cys405 is a redox-sensitive thiol that is necessary for ET\n                      <jats:sub>B<\/jats:sub>\n                      -eNOS signaling. In human pulmonary artery endothelial cells, mineralocorticoid receptor antagonism with spironolactone decreased aldosterone-mediated reactive oxygen species generation and restored ET\n                      <jats:sub>B<\/jats:sub>\n                      -dependent NO\n                      <jats:sup>\u00b7<\/jats:sup>\n                      production. Spironolactone or eplerenone prevented or reversed pulmonary vascular remodeling and improved cardiopulmonary hemodynamics in 2 animal models of PAH in vivo.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions\u2014<\/jats:title>\n                    <jats:p>\n                      Our findings demonstrate that aldosterone modulates an ET\n                      <jats:sub>B<\/jats:sub>\n                      cysteinyl thiol redox switch to decrease pulmonary endothelium-derived NO\n                      <jats:sup>\u00b7<\/jats:sup>\n                      and promote PAH.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1161\/circulationaha.112.094722","type":"journal-article","created":{"date-parts":[[2012,7,12]],"date-time":"2012-07-12T00:45:53Z","timestamp":1342053953000},"page":"963-974","update-policy":"https:\/\/doi.org\/10.1161\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":176,"title":["Aldosterone Inactivates the Endothelin-B Receptor via a Cysteinyl Thiol Redox Switch to Decrease Pulmonary Endothelial Nitric Oxide Levels and  Modulate Pulmonary Arterial Hypertension"],"prefix":"10.1161","volume":"126","author":[{"given":"Bradley A.","family":"Maron","sequence":"first","affiliation":[{"name":"From the Cardiovascular Division, Department of Medicine, Brigham and Women's Hospital &amp; Harvard Medical School, Boston, MA (B.A.M., Y.-Y.Z., K.W., S.Y.C., D.E.H., C.E.M., J.L., J.A.L.); and Department of Cardiology, Veterans Affairs Boston Healthcare System, West Roxbury, MA (B.A.M.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ying-Yi","family":"Zhang","sequence":"additional","affiliation":[{"name":"From the Cardiovascular Division, Department of Medicine, Brigham and Women's Hospital &amp; Harvard Medical School, Boston, MA (B.A.M., Y.-Y.Z., K.W., S.Y.C., D.E.H., C.E.M., J.L., J.A.L.); and Department of Cardiology, Veterans Affairs Boston Healthcare System, West Roxbury, MA (B.A.M.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kevin","family":"White","sequence":"additional","affiliation":[{"name":"From the Cardiovascular Division, Department of Medicine, Brigham and Women's Hospital &amp; Harvard Medical School, Boston, MA (B.A.M., Y.-Y.Z., K.W., S.Y.C., D.E.H., C.E.M., J.L., J.A.L.); and Department of Cardiology, Veterans Affairs Boston Healthcare System, West Roxbury, MA (B.A.M.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stephen Y.","family":"Chan","sequence":"additional","affiliation":[{"name":"From the Cardiovascular Division, Department of Medicine, Brigham and Women's Hospital &amp; Harvard Medical School, Boston, MA (B.A.M., Y.-Y.Z., K.W., S.Y.C., D.E.H., C.E.M., J.L., J.A.L.); and Department of Cardiology, Veterans Affairs Boston Healthcare System, West Roxbury, MA (B.A.M.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Diane E.","family":"Handy","sequence":"additional","affiliation":[{"name":"From the Cardiovascular Division, Department of Medicine, Brigham and Women's Hospital &amp; Harvard Medical School, Boston, MA (B.A.M., Y.-Y.Z., K.W., S.Y.C., D.E.H., C.E.M., J.L., J.A.L.); and Department of Cardiology, Veterans Affairs Boston Healthcare System, West Roxbury, MA (B.A.M.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christopher E.","family":"Mahoney","sequence":"additional","affiliation":[{"name":"From the Cardiovascular Division, Department of Medicine, Brigham and Women's Hospital &amp; Harvard Medical School, Boston, MA (B.A.M., Y.-Y.Z., K.W., S.Y.C., D.E.H., C.E.M., J.L., J.A.L.); and Department of Cardiology, Veterans Affairs Boston Healthcare System, West Roxbury, MA (B.A.M.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joseph","family":"Loscalzo","sequence":"additional","affiliation":[{"name":"From the Cardiovascular Division, Department of Medicine, Brigham and Women's Hospital &amp; Harvard Medical School, Boston, MA (B.A.M., Y.-Y.Z., K.W., S.Y.C., D.E.H., C.E.M., J.L., J.A.L.); and Department of Cardiology, Veterans Affairs Boston Healthcare System, West Roxbury, MA (B.A.M.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jane A.","family":"Leopold","sequence":"additional","affiliation":[{"name":"From the Cardiovascular Division, Department of Medicine, Brigham and Women's Hospital &amp; Harvard Medical School, Boston, MA (B.A.M., Y.-Y.Z., K.W., S.Y.C., D.E.H., C.E.M., J.L., J.A.L.); and Department of Cardiology, Veterans Affairs Boston Healthcare System, West Roxbury, MA (B.A.M.)."}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"276","reference":[{"key":"e_1_3_4_2_2","doi-asserted-by":"publisher","DOI":"10.1161\/circulationaha.108.847707"},{"key":"e_1_3_4_3_2","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMra035488"},{"key":"e_1_3_4_4_2","doi-asserted-by":"publisher","DOI":"10.1023\/A:1022150819223"},{"key":"e_1_3_4_5_2","doi-asserted-by":"publisher","DOI":"10.1038\/nm1545"},{"key":"e_1_3_4_6_2","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMra000050"},{"key":"e_1_3_4_7_2","doi-asserted-by":"publisher","DOI":"10.1210\/jcem.82.10.4279"},{"key":"e_1_3_4_8_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M809460200"},{"key":"e_1_3_4_9_2","doi-asserted-by":"publisher","DOI":"10.1172\/JCI116338"},{"key":"e_1_3_4_10_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.272.34.21589"},{"key":"e_1_3_4_11_2","doi-asserted-by":"publisher","DOI":"10.1161\/01.res.0000261658.12024.18"},{"key":"e_1_3_4_12_2","doi-asserted-by":"publisher","DOI":"10.1161\/circulationaha.107.748640"},{"key":"e_1_3_4_13_2","doi-asserted-by":"publisher","DOI":"10.1111\/j.1745-7254.2005.00214.x"},{"key":"e_1_3_4_14_2","doi-asserted-by":"publisher","DOI":"10.1152\/ajpheart.00281.2003"},{"key":"e_1_3_4_15_2","doi-asserted-by":"publisher","DOI":"10.1016\/0006-291X(89)92479-0"},{"key":"e_1_3_4_16_2","doi-asserted-by":"publisher","DOI":"10.1042\/BJ20100460"},{"key":"e_1_3_4_17_2","doi-asserted-by":"publisher","DOI":"10.1097\/01.fjc.0000211738.63207.c3"},{"key":"e_1_3_4_18_2","doi-asserted-by":"publisher","DOI":"10.1124\/mi.11.1.5"},{"key":"e_1_3_4_19_2","doi-asserted-by":"publisher","DOI":"10.1146\/annurev.pharmtox.41.1.851"},{"key":"e_1_3_4_20_2","doi-asserted-by":"publisher","DOI":"10.1021\/tx800463y"},{"key":"e_1_3_4_21_2","doi-asserted-by":"publisher","DOI":"10.1089\/ars.2010.3149"},{"key":"e_1_3_4_22_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M802455200"},{"key":"e_1_3_4_23_2","first-page":"33","article-title":"Activity of renin-angiotensin-aldosterone system (RAAS) and vasopressin level in patients with primary pulmonary hypertension [in Russian]","volume":"70","author":"Martyniuk TV","year":"1998","unstructured":"Martyniuk TV, Chazova IE, Masenko VP, Volkov VN, Belenkov IuN. 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