{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T11:22:20Z","timestamp":1790767340941,"version":"4.1.0"},"reference-count":49,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"17","content-domain":{"domain":["www.ahajournals.org"],"crossmark-restriction":true},"short-container-title":["Circulation"],"published-print":{"date-parts":[[2019,10,22]]},"abstract":"<jats:sec>\n                    <jats:title>Background:<\/jats:title>\n                    <jats:p>\n                      <jats:italic>Bmpr2<\/jats:italic>\n                      (bone morphogenetic protein receptor 2) mutations are critical risk factors for hereditary pulmonary arterial hypertension (PAH) with approximately 20% of carriers developing disease. There is an unmet medical need to understand how environmental factors, such as inflammation, render\n                      <jats:italic>Bmpr2<\/jats:italic>\n                      mutants susceptible to PAH. Overexpressing 5-LO (5-lipoxygenase) provokes lung inflammation and transient PAH in\n                      <jats:italic>Bmpr2<\/jats:italic>\n                      <jats:sup>\n                        <jats:italic>+\/<\/jats:italic>\n                        -\n                      <\/jats:sup>\n                      mice. Accordingly, 5-LO and its metabolite, leukotriene B\n                      <jats:sub>4<\/jats:sub>\n                      , are candidates for the second hit. The purpose of this study was to determine how 5-LO\u2013mediated pulmonary inflammation synergized with phenotypically silent\n                      <jats:italic>Bmpr2<\/jats:italic>\n                      defects to elicit significant pulmonary vascular disease in rats.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods:<\/jats:title>\n                    <jats:p>\n                      Monoallelic\n                      <jats:italic>Bmpr2<\/jats:italic>\n                      mutant rats were generated and found phenotypically normal for up to 1 year of observation. To evaluate whether a second hit would elicit disease, animals were exposed to 5-LO\u2013expressing adenovirus, monocrotaline, SU5416, SU5416 with chronic hypoxia, or chronic hypoxia alone.\n                      <jats:italic>Bmpr2<\/jats:italic>\n                      -mutant hereditary PAH patient samples were assessed for neointimal 5-LO expression. Pulmonary artery endothelial cells with impaired BMPR2 signaling were exposed to increased 5-LO\u2013mediated inflammation and were assessed for phenotypic and transcriptomic changes.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results:<\/jats:title>\n                    <jats:p>\n                      Lung inflammation, induced by intratracheal delivery of 5-LO\u2013expressing adenovirus, elicited severe PAH with intimal remodeling in\n                      <jats:italic>Bmpr2<\/jats:italic>\n                      <jats:sup>+\/-<\/jats:sup>\n                      rats but not in their wild-type littermates. Neointimal lesions in the diseased\n                      <jats:italic>Bmpr2<\/jats:italic>\n                      <jats:sup>+\/-<\/jats:sup>\n                      rats gained endogenous 5-LO expression associated with elevated leukotriene B\n                      <jats:sub>4<\/jats:sub>\n                      biosynthesis.\n                      <jats:italic>Bmpr2<\/jats:italic>\n                      -mutant hereditary PAH patients similarly expressed 5-LO in the neointimal cells. In vitro, BMPR2 deficiency, compounded by 5-LO\u2013mediated inflammation, generated apoptosis-resistant and proliferative pulmonary artery endothelial cells with mesenchymal characteristics. These transformed cells expressed nuclear envelope-localized 5-LO consistent with induced leukotriene B\n                      <jats:sub>4<\/jats:sub>\n                      production, as well as a transcriptomic signature similar to clinical disease, including upregulated nuclear factor Kappa B subunit (NF-\u03baB), interleukin-6, and transforming growth factor beta (TGF-\u03b2) signaling pathways. The reversal of PAH and vasculopathy in\n                      <jats:italic>Bmpr2<\/jats:italic>\n                      mutants by TGF-\u03b2 antagonism suggests that TGF-\u03b2 is critical for neointimal transformation.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions:<\/jats:title>\n                    <jats:p>\n                      In a new 2-hit model of disease, lung inflammation induced severe PAH pathology in\n                      <jats:italic>Bmpr2<\/jats:italic>\n                      <jats:sup>+\/-<\/jats:sup>\n                      rats. Endothelial transformation required the activation of canonical and noncanonical TGF-\u03b2 signaling pathways and was characterized by 5-LO nuclear envelope translocation with enhanced leukotriene B\n                      <jats:sub>4<\/jats:sub>\n                      production. This study offers an explanation of how an environmental injury unleashes the destructive potential of an otherwise silent genetic mutation.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1161\/circulationaha.119.040629","type":"journal-article","created":{"date-parts":[[2019,8,29]],"date-time":"2019-08-29T05:00:35Z","timestamp":1567054835000},"page":"1409-1425","update-policy":"https:\/\/doi.org\/10.1161\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":84,"title":["Phenotypically Silent Bone Morphogenetic Protein Receptor 2 Mutations Predispose Rats to Inflammation-Induced Pulmonary Arterial Hypertension by Enhancing the Risk for Neointimal Transformation"],"prefix":"10.1161","volume":"140","author":[{"given":"Wen","family":"Tian","sequence":"first","affiliation":[{"name":"Veterans Affairs Palo Alto Health Care System, CA (W.T, X.J., Y.K.S., E.S., A.B.T., G.P., Y.K., P.Z., S.P., P.D., M.R.N.)."},{"name":"Stanford University School of Medicine, CA (W.T., X.J., Y.K.S., E.S., T.H.W., P.N.K., A.B.T., A.C., L.W., G.P., Y.K., P.Z., J.C., S.P., P.D., P.M., H.C., R.Z., M.P.S., M.R., M.R.N.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xinguo","family":"Jiang","sequence":"additional","affiliation":[{"name":"Veterans Affairs Palo Alto Health Care System, CA (W.T, X.J., Y.K.S., E.S., A.B.T., G.P., Y.K., P.Z., S.P., P.D., M.R.N.)."},{"name":"Stanford University School of Medicine, CA (W.T., X.J., Y.K.S., E.S., T.H.W., P.N.K., A.B.T., A.C., L.W., G.P., Y.K., P.Z., J.C., S.P., P.D., P.M., H.C., R.Z., M.P.S., M.R., M.R.N.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yon K.","family":"Sung","sequence":"additional","affiliation":[{"name":"Veterans Affairs Palo Alto Health Care System, CA (W.T, X.J., Y.K.S., E.S., A.B.T., G.P., Y.K., P.Z., S.P., P.D., M.R.N.)."},{"name":"Stanford University School of Medicine, CA (W.T., X.J., Y.K.S., E.S., T.H.W., P.N.K., A.B.T., A.C., L.W., G.P., Y.K., P.Z., J.C., 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