{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,23]],"date-time":"2026-10-23T04:40:56Z","timestamp":1792730456505,"version":"4.5.0"},"reference-count":39,"publisher":"National Academy of Sciences","issue":"27","content-domain":{"domain":["www.pnas.org"],"crossmark-restriction":true},"short-container-title":["Proc. Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2007,7,3]]},"abstract":"\n In pulmonary arterial hypertension (PAH), antiapoptotic, proliferative, and inflammatory diatheses converge to create an obstructive vasculopathy. A selective down-regulation of the Kv channel Kv1.5 has been described in human and animal PAH. The resultant increase in intracellular free Ca\n 2+<\/jats:sup>\n ([Ca\n 2+<\/jats:sup>\n ]\n i<\/jats:sub>\n ) and K\n +<\/jats:sup>\n ([K\n +<\/jats:sup>\n ]\n i<\/jats:sub>\n ) concentrations explains the pulmonary artery smooth muscle cell (PASMC) contraction, proliferation and resistance to apoptosis. The recently described PASMC hyperpolarized mitochondria and increased bcl-2 levels also contribute to apoptosis resistance in PAH. The cause of the Kv1.5, mitochondrial, and inflammatory abnormalities remains unknown. We hypothesized that these abnormalities can be explained in part by an activation of NFAT (nuclear factor of activated T cells), a Ca\n 2+<\/jats:sup>\n \/calcineurin-sensitive transcription factor. We studied PASMC and lungs from six patients with and four without PAH and blood from 23 PAH patients and 10 healthy volunteers. Compared with normal, PAH PASMC had decreased Kv current and Kv1.5 expression and increased [Ca\n 2+<\/jats:sup>\n ]\n i<\/jats:sub>\n , [K\n +<\/jats:sup>\n ]\n i<\/jats:sub>\n , mitochondrial potential (\u0394\u03a8m), and bcl-2 levels. PAH but not normal PASMC and lungs showed activation of NFATc2. Inhibition of NFATc2 by VIVIT or cyclosporine restored Kv1.5 expression and current, decreased [Ca\n 2+<\/jats:sup>\n ]\n i<\/jats:sub>\n , [K\n +<\/jats:sup>\n ]\n i<\/jats:sub>\n , bcl-2, and \u0394\u03a8m, leading to decreased proliferation and increased apoptosis\n in vitro. In vivo<\/jats:italic>\n , cyclosporine decreased established rat monocrotaline-PAH. NFATc2 levels were increased in circulating leukocytes in PAH versus healthy volunteers. CD3-positive lymphocytes with activated NFATc2 were seen in the arterial wall in PAH but not normal lungs. The generalized activation of NFAT in human and experimental PAH might regulate the ionic, mitochondrial, and inflammatory remodeling and be a therapeutic target and biomarker.\n <\/jats:p>","DOI":"10.1073\/pnas.0610467104","type":"journal-article","created":{"date-parts":[[2007,6,28]],"date-time":"2007-06-28T00:41:59Z","timestamp":1182991319000},"page":"11418-11423","update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":332,"title":["The nuclear factor of activated T cells in pulmonary arterial hypertension can be therapeutically targeted"],"prefix":"10.1073","volume":"104","author":[{"given":"Sebastien","family":"Bonnet","sequence":"first","affiliation":[{"name":"*Pulmonary Hypertension Program, University of Alberta, Edmonton, AB, Canada IGG 2B7; and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gael","family":"Rochefort","sequence":"additional","affiliation":[{"name":"LABRART E. A. 3852 Universite Francois-Rubelais Unit\u00e9 de Formation et de Recherche Medecine, 37032 Tours, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gopinath","family":"Sutendra","sequence":"additional","affiliation":[{"name":"*Pulmonary Hypertension Program, University of Alberta, Edmonton, AB, Canada IGG 2B7; and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stephen L.","family":"Archer","sequence":"additional","affiliation":[{"name":"*Pulmonary Hypertension Program, University of Alberta, Edmonton, AB, Canada IGG 2B7; and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alois","family":"Haromy","sequence":"additional","affiliation":[{"name":"*Pulmonary Hypertension Program, University of Alberta, Edmonton, AB, Canada IGG 2B7; and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Linda","family":"Webster","sequence":"additional","affiliation":[{"name":"*Pulmonary Hypertension Program, University of Alberta, Edmonton, AB, Canada IGG 2B7; and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kyoko","family":"Hashimoto","sequence":"additional","affiliation":[{"name":"*Pulmonary Hypertension Program, University of Alberta, Edmonton, AB, Canada IGG 2B7; and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sandra N.","family":"Bonnet","sequence":"additional","affiliation":[{"name":"*Pulmonary Hypertension Program, University of Alberta, Edmonton, AB, Canada IGG 2B7; and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Evangelos D.","family":"Michelakis","sequence":"additional","affiliation":[{"name":"*Pulmonary Hypertension Program, University of Alberta, Edmonton, AB, Canada IGG 2B7; 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