{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,6]],"date-time":"2026-10-06T00:39:07Z","timestamp":1791247147166,"version":"4.1.0"},"reference-count":45,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"1","content-domain":{"domain":["www.ahajournals.org"],"crossmark-restriction":true},"short-container-title":["JAHA"],"published-print":{"date-parts":[[2013,1,23]]},"abstract":"\n Background<\/jats:title>\n \n Pulmonary arterial hypertension (\n PAH<\/jats:styled-content>\n ) is a vasculopathy characterized by enhanced pulmonary artery smooth muscle cell (\n PASMC<\/jats:styled-content>\n ) proliferation and suppressed apoptosis. This results in both increase in pulmonary arterial pressure and pulmonary vascular resistance. Recent studies have shown the implication of the signal transducer and activator of transcription 3 (\n STAT<\/jats:styled-content>\n 3)\/bone morphogenetic protein receptor 2 (\n BMPR<\/jats:styled-content>\n 2)\/peroxisome proliferator\u2010activated receptor gamma (\n PPAR<\/jats:styled-content>\n \u03b3) in\n PAH<\/jats:styled-content>\n .\n STAT<\/jats:styled-content>\n 3 activation induces\n BMPR<\/jats:styled-content>\n 2 downregulation, decreasing\n PPAR<\/jats:styled-content>\n \u03b3, which both contribute to the proproliferative and antiapoptotic phenotype seen in\n PAH<\/jats:styled-content>\n . In chondrocytes, activation of this axis has been attributed to the advanced glycation end\u2010products receptor (\n RAGE<\/jats:styled-content>\n ). As\n RAGE<\/jats:styled-content>\n is one of the most upregulated proteins in\n PAH<\/jats:styled-content>\n patients' lungs and a strong\n STAT<\/jats:styled-content>\n 3 activator, we hypothesized that by activating\n STAT<\/jats:styled-content>\n 3,\n RAGE<\/jats:styled-content>\n induces\n BMPR<\/jats:styled-content>\n 2 and\n PPAR<\/jats:styled-content>\n \u03b3 downregulation, promoting\n PAH<\/jats:styled-content>\n \u2010\n PASMC<\/jats:styled-content>\n proliferation and resistance to apoptosis.\n <\/jats:p>\n <\/jats:sec>\n \n Methods and Results<\/jats:title>\n \n In vitro, using\n PASMC<\/jats:styled-content>\n s isolated from\n PAH<\/jats:styled-content>\n and healthy patients, we demonstrated that\n RAGE<\/jats:styled-content>\n is overexpressed in\n PAH<\/jats:styled-content>\n \u2010\n PASMC<\/jats:styled-content>\n (6\u2010fold increase), thus inducing\n STAT<\/jats:styled-content>\n 3 activation (from 10% to 40% positive cells) and decrease in\n BMPR<\/jats:styled-content>\n 2 and\n PPAR<\/jats:styled-content>\n \u03b3 levels (>50% decrease). Pharmacological activation of\n RAGE<\/jats:styled-content>\n in control cells by S100A4 recapitulates the\n PAH<\/jats:styled-content>\n phenotype (increasing\n RAGE<\/jats:styled-content>\n by 6\u2010fold, thus activating\n STAT<\/jats:styled-content>\n 3 and decreasing\n BMPR<\/jats:styled-content>\n 2 and\n PPAR<\/jats:styled-content>\n \u03b3). In both conditions, this phenotype is totally reversed on\n RAGE<\/jats:styled-content>\n inhibition. In vivo,\n RAGE<\/jats:styled-content>\n inhibition in monocrotaline\u2010 and\n S<\/jats:styled-content>\n ugen\u2010induced\n PAH<\/jats:styled-content>\n demonstrates therapeutic effects characterized by\n PA<\/jats:styled-content>\n pressure and right ventricular hypertrophy decrease (control rats have an\n mPAP<\/jats:styled-content>\n around 15\u00a0mm\u00a0Hg,\n PAH<\/jats:styled-content>\n rats have an\n mPAP<\/jats:styled-content>\n >40\u00a0mm\u00a0Hg, and with\n RAGE<\/jats:styled-content>\n inhibition,\n mPAP<\/jats:styled-content>\n decreases to 20 and 28\u00a0mm\u00a0Hg, respectively, in\n MCT<\/jats:styled-content>\n and\n S<\/jats:styled-content>\n ugen models). This was associated with significant improvement in lung perfusion and vascular remodeling due to decrease in proliferation (>50% decrease) and\n BMPR<\/jats:styled-content>\n 2\/\n PPAR<\/jats:styled-content>\n \u03b3 axis restoration (increased by \u226560%).\n <\/jats:p>\n <\/jats:sec>\n \n Conclusion<\/jats:title>\n \n We have demonstrated the implications of\n RAGE<\/jats:styled-content>\n in\n PAH<\/jats:styled-content>\n etiology. Thus,\n RAGE<\/jats:styled-content>\n constitutes a new attractive therapeutic target for\n PAH<\/jats:styled-content>\n .\n <\/jats:p>\n <\/jats:sec>","DOI":"10.1161\/jaha.112.005157","type":"journal-article","created":{"date-parts":[[2013,5,24]],"date-time":"2013-05-24T16:49:11Z","timestamp":1369414151000},"update-policy":"https:\/\/doi.org\/10.1161\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":86,"title":["Critical Role for the Advanced Glycation End\u2010Products Receptor in Pulmonary Arterial Hypertension Etiology"],"prefix":"10.1161","volume":"2","author":[{"given":"Jolyane","family":"Meloche","sequence":"first","affiliation":[{"name":"Pulmonary Hypertension Group of the Institut universitaire de cardiologie et de pneumologie de Qu\u00e9bec, Laval University, Quebec City, Canada"},{"name":"Institut universitaire de cardiologie et de pneumologie de Qu\u00e9bec, Quebec City, 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Quebec City, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Malik","family":"Bisserier","sequence":"additional","affiliation":[{"name":"Pulmonary Hypertension Group of the Institut universitaire de cardiologie et de pneumologie de Qu\u00e9bec, Laval University, Quebec City, Canada"},{"name":"Institut universitaire de cardiologie et de pneumologie de Qu\u00e9bec, Quebec City, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Roxane","family":"Paulin","sequence":"additional","affiliation":[{"name":"Pulmonary Hypertension Group of the Institut universitaire de cardiologie et de pneumologie de Qu\u00e9bec, Laval University, Quebec City, Canada"},{"name":"Institut universitaire de cardiologie et de pneumologie de Qu\u00e9bec, Quebec City, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jean\u2010Fran\u00e7ois","family":"Lauzon\u2010Joset","sequence":"additional","affiliation":[{"name":"Institut universitaire de 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