دورية أكاديمية
Phenotypically Silent Bone Morphogenetic Protein Receptor 2 Mutations Predispose Rats to Inflammation-Induced Pulmonary Arterial Hypertension by Enhancing the Risk for Neointimal Transformation.
العنوان: | Phenotypically Silent Bone Morphogenetic Protein Receptor 2 Mutations Predispose Rats to Inflammation-Induced Pulmonary Arterial Hypertension by Enhancing the Risk for Neointimal Transformation. |
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المؤلفون: | Tian W; 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.).; 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.)., Jiang X; 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.).; 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.)., Sung YK; 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.).; 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.)., Shuffle E; 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.).; 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.)., Wu TH; 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.)., Kao PN; 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.)., Tu AB; 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.).; 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.)., Dorfmüller P; Faculté de Médecine, Université Paris-Sud and Université Paris-Saclay, Le Kremlin-Bicêtre, France (P.D., M.H.).; Institut National de la Sante Et de la Recherche Medicale UMR_S 999, Le Plessis-Robinson, France (P.D., M.H.).; Pathology Department, Hôpital Marie Lannelongue, Le Plessis-Robinson, Paris, France (P.D.)., Cao A; 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.)., Wang L; 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.)., Peng G; 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.).; 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.).; State Key Laboratory of Respiratory Diseases, Guangzhou Institute of Respiratory Health, The First Affiliated Hospital of Guangzhou Medical University, China (G.P.)., Kim Y; 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.).; 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.)., Zhang P; 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.).; 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.)., Chappell J; 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.)., Pasupneti S; 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.).; 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.)., Dahms P; 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.).; 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.)., Maguire P; 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.)., Chaib H; 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.)., Zamanian R; 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.)., Peters-Golden M; University of Michigan Health System, Ann Arbor (M.P.G.)., Snyder MP; 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.)., Voelkel NF; Free University Medical Center Amsterdam, the Netherlands (N.F.V.)., Humbert M; Faculté de Médecine, Université Paris-Sud and Université Paris-Saclay, Le Kremlin-Bicêtre, France (P.D., M.H.).; Institut National de la Sante Et de la Recherche Medicale UMR_S 999, Le Plessis-Robinson, France (P.D., M.H.).; AP-HP, Service de Pneumologie, Centre de Référence de l'Hypertension Pulmonaire Sévère, Department Hospitalo-Universitaire Thorax Innovation, Hôpital de Bicêtre, Le Kremlin-Bicêtre, France (M.H.)., Rabinovitch M; 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.)., Nicolls MR; 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.).; 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.). |
المصدر: | Circulation [Circulation] 2019 Oct 22; Vol. 140 (17), pp. 1409-1425. Date of Electronic Publication: 2019 Aug 29. |
نوع المنشور: | Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't |
اللغة: | English |
بيانات الدورية: | Publisher: Lippincott Williams & Wilkins Country of Publication: United States NLM ID: 0147763 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1524-4539 (Electronic) Linking ISSN: 00097322 NLM ISO Abbreviation: Circulation Subsets: MEDLINE |
أسماء مطبوعة: | Publication: Hagerstown, MD : Lippincott Williams & Wilkins Original Publication: [Dallas, Tex., etc., American Heart Association, etc.] |
مواضيع طبية MeSH: | Bone Morphogenetic Protein Receptors, Type II/*genetics , Inflammation/*metabolism , Neointima/*metabolism , Pulmonary Arterial Hypertension/*physiopathology, Animals ; Endothelial Cells/metabolism ; Hypertension, Pulmonary/physiopathology ; Myocytes, Smooth Muscle/metabolism ; Pulmonary Arterial Hypertension/genetics ; Pulmonary Artery/pathology ; Pulmonary Artery/physiopathology ; Rats, Transgenic ; Signal Transduction/physiology |
مستخلص: | Background: Bmpr2 (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 Bmpr2 mutants susceptible to PAH. Overexpressing 5-LO (5-lipoxygenase) provokes lung inflammation and transient PAH in Bmpr2 +/ - mice. Accordingly, 5-LO and its metabolite, leukotriene B Methods: Monoallelic Bmpr2 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-expressing adenovirus, monocrotaline, SU5416, SU5416 with chronic hypoxia, or chronic hypoxia alone. Bmpr2 -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-mediated inflammation and were assessed for phenotypic and transcriptomic changes. Results: Lung inflammation, induced by intratracheal delivery of 5-LO-expressing adenovirus, elicited severe PAH with intimal remodeling in Bmpr2 +/- rats but not in their wild-type littermates. Neointimal lesions in the diseased Bmpr2 +/- rats gained endogenous 5-LO expression associated with elevated leukotriene B Conclusions: In a new 2-hit model of disease, lung inflammation induced severe PAH pathology in Bmpr2 +/- rats. Endothelial transformation required the activation of canonical and noncanonical TGF-β signaling pathways and was characterized by 5-LO nuclear envelope translocation with enhanced leukotriene B |
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معلومات مُعتمدة: | R01 HL095686 United States HL NHLBI NIH HHS; R01 HL138473 United States HL NHLBI NIH HHS; R01 HL074186 United States HL NHLBI NIH HHS; R56 HL082662 United States HL NHLBI NIH HHS; K12 HL120001 United States HL NHLBI NIH HHS; R01 HL122887 United States HL NHLBI NIH HHS; T32 HL129970 United States HL NHLBI NIH HHS; S10 OD020141 United States OD NIH HHS; R01 HL125739 United States HL NHLBI NIH HHS; R01 HL082662 United States HL NHLBI NIH HHS; P01 HL014985 United States HL NHLBI NIH HHS |
فهرسة مساهمة: | Keywords: bmpr2 receptor; endothelial cells; inflammation; lung |
المشرفين على المادة: | EC 2.7.11.30 (Bone Morphogenetic Protein Receptors, Type II) |
تواريخ الأحداث: | Date Created: 20190830 Date Completed: 20200617 Latest Revision: 20201022 |
رمز التحديث: | 20240829 |
مُعرف محوري في PubMed: | PMC6803052 |
DOI: | 10.1161/CIRCULATIONAHA.119.040629 |
PMID: | 31462075 |
قاعدة البيانات: | MEDLINE |
تدمد: | 1524-4539 |
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DOI: | 10.1161/CIRCULATIONAHA.119.040629 |