ArticleCirculation2016
Estrogen Metabolite 16α-Hydroxyestrone Exacerbates Bone Morphogenetic Protein Receptor Type II-Associated Pulmonary Arterial Hypertension Through MicroRNA-29-Mediated Modulation of Cellular Metabolism.
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Article in Circulation, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 63 papers.
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63 citing papers in PubMed.
- The Role of Exosomes in Pulmonary Hypertension: Mechanisms and Therapeutic Potential.International journal of nanomedicine · 2026Review
- Sex-specific insights in atherosclerosis and pulmonary arterial hypertension: an overlooked comorbidity.Frontiers in cardiovascular medicine · 2026Review
- Signaling pathways and targeted therapy for pulmonary hypertension.Signal transduction and targeted therapy · 2025Review
- Decoding the enigmatic estrogen paradox in pulmonary hypertension: delving into estrogen metabolites and metabolic enzymes.Cellular & molecular biology letters · 2024Review
- Review
- Interaction of estradiol and renin-angiotensin system with microRNAs-21 and -29 in renal fibrosis: focus on TGF-β/smad signaling pathway.Molecular biology reports · 2024Review
- Epigenetics of hypertension as a risk factor for the development of coronary artery disease in type 2 diabetes mellitus.Frontiers in endocrinology · 2024Review
- Review
- HIV and Drug Use: A Tale of Synergy in Pulmonary Vascular Disease Development.Comprehensive Physiology · 2023Article
- MicroRNA and lncRNA as the Future of Pulmonary Arterial Hypertension Treatment.International journal of molecular sciences · 2023Review
- SOX17 Deficiency Mediates Pulmonary Hypertension: At the Crossroads of Sex, Metabolism, and Genetics.American journal of respiratory and critical care medicine · 2023Article
- Multiomics endotyping of preterm infants with bronchopulmonary dysplasia and pulmonary hypertension-A pilot study.Pulmonary circulation · 2023Article
- Role of miR-21-5p/FilGAP axis in estradiol alleviating the progression of monocrotaline-induced pulmonary hypertension.Animal models and experimental medicine · 2022Article
- Sex and gender in pulmonary arterial hypertension.European respiratory review : an official journal of the European Respiratory Society · 2021Review
- The role of TGF-β or BMPR2 signaling pathway-related miRNA in pulmonary arterial hypertension and systemic sclerosis.Arthritis research & therapy · 2021Review
- hsa_circNFXL1_009 modulates apoptosis, proliferation, migration, and potassium channel activation in pulmonary hypertension.Molecular therapy. Nucleic acids · 2021Article
- Insights from the Menstrual Cycle in Pulmonary Arterial Hypertension.Annals of the American Thoracic Society · 2021Observational
- An Overview of miRNAs Involved in PASMC Phenotypic Switching in Pulmonary Hypertension.BioMed research international · 2021Review
- Cardiac and Pulmonary Vascular Remodeling in Endurance Open Water Swimmers Assessed by Cardiac Magnetic Resonance: Impact of Sex and Sport Discipline.Frontiers in cardiovascular medicine · 2021Article
- DNA methyltransferase 3B deficiency unveils a new pathological mechanism of pulmonary hypertension.Science advances · 2020Article
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Authors and funding
20 authors.
Xinping ChenFrom Departments of Medicine (X.C., M.T., J.P.F., A.R.H., S.G., J.F., S.S., L.A.W., J.E.L., S.J.M., J.W.), Pharmacology (J.P.F.), Pediatrics (J.A.P., R.H., J..C., L.K.H.), and Pathology (E.G.M.), Vanderbilt University Medical Center, Nashville, TN; Department of Medicine, Baylor College of Medicine, Houston, TX (A.T.); and Bioventures, Inc, Murfreesboro, TN (E.P.D., K.E.W.).
Megha TalatiFrom Departments of Medicine (X.C., M.T., J.P.F., A.R.H., S.G., J.F., S.S., L.A.W., J.E.L., S.J.M., J.W.), Pharmacology (J.P.F.), Pediatrics (J.A.P., R.H., J..C., L.K.H.), and Pathology (E.G.M.), Vanderbilt University Medical Center, Nashville, TN; Department of Medicine, Baylor College of Medicine, Houston, TX (A.T.); and Bioventures, Inc, Murfreesboro, TN (E.P.D., K.E.W.).
Joshua P FesselFrom Departments of Medicine (X.C., M.T., J.P.F., A.R.H., S.G., J.F., S.S., L.A.W., J.E.L., S.J.M., J.W.), Pharmacology (J.P.F.), Pediatrics (J.A.P., R.H., J..C., L.K.H.), and Pathology (E.G.M.), Vanderbilt University Medical Center, Nashville, TN; Department of Medicine, Baylor College of Medicine, Houston, TX (A.T.); and Bioventures, Inc, Murfreesboro, TN (E.P.D., K.E.W.).
Anna R HemnesFrom Departments of Medicine (X.C., M.T., J.P.F., A.R.H., S.G., J.F., S.S., L.A.W., J.E.L., S.J.M., J.W.), Pharmacology (J.P.F.), Pediatrics (J.A.P., R.H., J..C., L.K.H.), and Pathology (E.G.M.), Vanderbilt University Medical Center, Nashville, TN; Department of Medicine, Baylor College of Medicine, Houston, TX (A.T.); and Bioventures, Inc, Murfreesboro, TN (E.P.D., K.E.W.).
Santhi GladsonFrom Departments of Medicine (X.C., M.T., J.P.F., A.R.H., S.G., J.F., S.S., L.A.W., J.E.L., S.J.M., J.W.), Pharmacology (J.P.F.), Pediatrics (J.A.P., R.H., J..C., L.K.H.), and Pathology (E.G.M.), Vanderbilt University Medical Center, Nashville, TN; Department of Medicine, Baylor College of Medicine, Houston, TX (A.T.); and Bioventures, Inc, Murfreesboro, TN (E.P.D., K.E.W.).
Jaketa FrenchFrom Departments of Medicine (X.C., M.T., J.P.F., A.R.H., S.G., J.F., S.S., L.A.W., J.E.L., S.J.M., J.W.), Pharmacology (J.P.F.), Pediatrics (J.A.P., R.H., J..C., L.K.H.), and Pathology (E.G.M.), Vanderbilt University Medical Center, Nashville, TN; Department of Medicine, Baylor College of Medicine, Houston, TX (A.T.); and Bioventures, Inc, Murfreesboro, TN (E.P.D., K.E.W.).
Sheila ShayFrom Departments of Medicine (X.C., M.T., J.P.F., A.R.H., S.G., J.F., S.S., L.A.W., J.E.L., S.J.M., J.W.), Pharmacology (J.P.F.), Pediatrics (J.A.P., R.H., J..C., L.K.H.), and Pathology (E.G.M.), Vanderbilt University Medical Center, Nashville, TN; Department of Medicine, Baylor College of Medicine, Houston, TX (A.T.); and Bioventures, Inc, Murfreesboro, TN (E.P.D., K.E.W.).
Aaron TrammellFrom Departments of Medicine (X.C., M.T., J.P.F., A.R.H., S.G., J.F., S.S., L.A.W., J.E.L., S.J.M., J.W.), Pharmacology (J.P.F.), Pediatrics (J.A.P., R.H., J..C., L.K.H.), and Pathology (E.G.M.), Vanderbilt University Medical Center, Nashville, TN; Department of Medicine, Baylor College of Medicine, Houston, TX (A.T.); and Bioventures, Inc, Murfreesboro, TN (E.P.D., K.E.W.).
John A PhillipsFrom Departments of Medicine (X.C., M.T., J.P.F., A.R.H., S.G., J.F., S.S., L.A.W., J.E.L., S.J.M., J.W.), Pharmacology (J.P.F.), Pediatrics (J.A.P., R.H., J..C., L.K.H.), and Pathology (E.G.M.), Vanderbilt University Medical Center, Nashville, TN; Department of Medicine, Baylor College of Medicine, Houston, TX (A.T.); and Bioventures, Inc, Murfreesboro, TN (E.P.D., K.E.W.).
Rizwan HamidFrom Departments of Medicine (X.C., M.T., J.P.F., A.R.H., S.G., J.F., S.S., L.A.W., J.E.L., S.J.M., J.W.), Pharmacology (J.P.F.), Pediatrics (J.A.P., R.H., J..C., L.K.H.), and Pathology (E.G.M.), Vanderbilt University Medical Center, Nashville, TN; Department of Medicine, Baylor College of Medicine, Houston, TX (A.T.); and Bioventures, Inc, Murfreesboro, TN (E.P.D., K.E.W.).
Joy D CoganFrom Departments of Medicine (X.C., M.T., J.P.F., A.R.H., S.G., J.F., S.S., L.A.W., J.E.L., S.J.M., J.W.), Pharmacology (J.P.F.), Pediatrics (J.A.P., R.H., J..C., L.K.H.), and Pathology (E.G.M.), Vanderbilt University Medical Center, Nashville, TN; Department of Medicine, Baylor College of Medicine, Houston, TX (A.T.); and Bioventures, Inc, Murfreesboro, TN (E.P.D., K.E.W.).
Elliott P DawsonFrom Departments of Medicine (X.C., M.T., J.P.F., A.R.H., S.G., J.F., S.S., L.A.W., J.E.L., S.J.M., J.W.), Pharmacology (J.P.F.), Pediatrics (J.A.P., R.H., J..C., L.K.H.), and Pathology (E.G.M.), Vanderbilt University Medical Center, Nashville, TN; Department of Medicine, Baylor College of Medicine, Houston, TX (A.T.); and Bioventures, Inc, Murfreesboro, TN (E.P.D., K.E.W.).
Kristie E WombleFrom Departments of Medicine (X.C., M.T., J.P.F., A.R.H., S.G., J.F., S.S., L.A.W., J.E.L., S.J.M., J.W.), Pharmacology (J.P.F.), Pediatrics (J.A.P., R.H., J..C., L.K.H.), and Pathology (E.G.M.), Vanderbilt University Medical Center, Nashville, TN; Department of Medicine, Baylor College of Medicine, Houston, TX (A.T.); and Bioventures, Inc, Murfreesboro, TN (E.P.D., K.E.W.).
Lora K HedgesFrom Departments of Medicine (X.C., M.T., J.P.F., A.R.H., S.G., J.F., S.S., L.A.W., J.E.L., S.J.M., J.W.), Pharmacology (J.P.F.), Pediatrics (J.A.P., R.H., J..C., L.K.H.), and Pathology (E.G.M.), Vanderbilt University Medical Center, Nashville, TN; Department of Medicine, Baylor College of Medicine, Houston, TX (A.T.); and Bioventures, Inc, Murfreesboro, TN (E.P.D., K.E.W.).
Elizabeth G MartinezFrom Departments of Medicine (X.C., M.T., J.P.F., A.R.H., S.G., J.F., S.S., L.A.W., J.E.L., S.J.M., J.W.), Pharmacology (J.P.F.), Pediatrics (J.A.P., R.H., J..C., L.K.H.), and Pathology (E.G.M.), Vanderbilt University Medical Center, Nashville, TN; Department of Medicine, Baylor College of Medicine, Houston, TX (A.T.); and Bioventures, Inc, Murfreesboro, TN (E.P.D., K.E.W.).
Lisa A WheelerFrom Departments of Medicine (X.C., M.T., J.P.F., A.R.H., S.G., J.F., S.S., L.A.W., J.E.L., S.J.M., J.W.), Pharmacology (J.P.F.), Pediatrics (J.A.P., R.H., J..C., L.K.H.), and Pathology (E.G.M.), Vanderbilt University Medical Center, Nashville, TN; Department of Medicine, Baylor College of Medicine, Houston, TX (A.T.); and Bioventures, Inc, Murfreesboro, TN (E.P.D., K.E.W.).
James E LoydFrom Departments of Medicine (X.C., M.T., J.P.F., A.R.H., S.G., J.F., S.S., L.A.W., J.E.L., S.J.M., J.W.), Pharmacology (J.P.F.), Pediatrics (J.A.P., R.H., J..C., L.K.H.), and Pathology (E.G.M.), Vanderbilt University Medical Center, Nashville, TN; Department of Medicine, Baylor College of Medicine, Houston, TX (A.T.); and Bioventures, Inc, Murfreesboro, TN (E.P.D., K.E.W.).
Susan J MajkaFrom Departments of Medicine (X.C., M.T., J.P.F., A.R.H., S.G., J.F., S.S., L.A.W., J.E.L., S.J.M., J.W.), Pharmacology (J.P.F.), Pediatrics (J.A.P., R.H., J..C., L.K.H.), and Pathology (E.G.M.), Vanderbilt University Medical Center, Nashville, TN; Department of Medicine, Baylor College of Medicine, Houston, TX (A.T.); and Bioventures, Inc, Murfreesboro, TN (E.P.D., K.E.W.).
James WestFrom Departments of Medicine (X.C., M.T., J.P.F., A.R.H., S.G., J.F., S.S., L.A.W., J.E.L., S.J.M., J.W.), Pharmacology (J.P.F.), Pediatrics (J.A.P., R.H., J..C., L.K.H.), and Pathology (E.G.M.), Vanderbilt University Medical Center, Nashville, TN; Department of Medicine, Baylor College of Medicine, Houston, TX (A.T.); and Bioventures, Inc, Murfreesboro, TN (E.P.D., K.E.W.).
Eric D AustinFrom Departments of Medicine (X.C., M.T., J.P.F., A.R.H., S.G., J.F., S.S., L.A.W., J.E.L., S.J.M., J.W.), Pharmacology (J.P.F.), Pediatrics (J.A.P., R.H., J..C., L.K.H.), and Pathology (E.G.M.), Vanderbilt University Medical Center, Nashville, TN; Department of Medicine, Baylor College of Medicine, Houston, TX (A.T.); and Bioventures, Inc, Murfreesboro, TN (E.P.D., K.E.W.). eric.austin@vanderbilt.edu.
Funding
The Vanderbilt Institute for Clinical and Translational Research (VICTR)UL1TR000445 · NCATS · VANDERBILT UNIVERSITY MEDICAL CENTER · PI BERNARD, GORDON RAPHAEL · 2012 to 2016
$41.4MSex Hormones in Pulmonary Arterial HypertensionP01HL108800 · NHLBI · VANDERBILT UNIVERSITY MEDICAL CENTER · PI LOYD, JAMES E · 2012 to 2021
$22.0MVanderbilt Center for Undiagnosed Diseases (VCUD) - BiorepositoryU01HG007674 · NHGRI · VANDERBILT UNIVERSITY MEDICAL CENTER · PI COGAN, JOY D, HAMID, RIZWAN · 2014 to 2022
$13.7MInterventions Against the Molecular Etiology of BMPR2-induced PAHR01HL095797 · NHLBI · VANDERBILT UNIVERSITY MEDICAL CENTER · PI WEST, JAMES D · 2010 to 2022
$6.7MInterdisciplinary Training Program in Lung ResearchT32HL094296 · NHLBI · VANDERBILT UNIVERSITY MEDICAL CENTER · PI Ray Stokes Peebles · 2008 to 2026
$6.3MRole of Lung MSC in EmphysemaR01HL116597 · NHLBI · VANDERBILT UNIVERSITY MEDICAL CENTER · PI MAJKA, SUSAN M · 2013 to 2021
$4.4MRole of BMPR2 expression in HPAH; implications for novel therapeutic approachesR01HL102020 · NHLBI · VANDERBILT UNIVERSITY MEDICAL CENTER · PI HAMID, RIZWAN · 2011 to 2015
$2.3MMetabolic Reprogramming in Pulmonary Arterial HypertensionK08HL121174 · NHLBI · VANDERBILT UNIVERSITY MEDICAL CENTER · PI FESSEL, JOSHUA PATRICK · 2014 to 2018
$723kVariations in estrogen exposures may modify pulmonary arterial hypertensionK23HL098743 · NHLBI · VANDERBILT UNIVERSITY · PI AUSTIN, ERIC DOUGLAS · 2010 to 2014
$652kGender differences and endothelin responses in right ventricular afterload stressK08HL093363 · NHLBI · VANDERBILT UNIVERSITY · PI HEMNES, ANNA R · 2008 to 2012
$627kXFe96 AnalyzerS10OD018015 · OD · VANDERBILT UNIVERSITY · PI LANNIGAN, DEBORAH · 2014 to 2014
$200kNCATS NIH HHS UL1 TR000445NCATS NIH HHS UL1TR000445NHGRI NIH HHS U01 HG007674NHLBI NIH HHS K08 HL 093363NHLBI NIH HHS K08 HL093363NHLBI NIH HHS K08 HL121174NHLBI NIH HHS K23 HL 098743NHLBI NIH HHS K23 HL098743NHLBI NIH HHS L40 HL090173NHLBI NIH HHS P01 HL 108800NHLBI NIH HHS P01 HL108800NHLBI NIH HHS R01 HL095797NHLBI NIH HHS R01 HL102020NHLBI NIH HHS R01 HL116597NHLBI NIH HHS T32 HL094296NIH HHS S10 OD018015
Abstract
backgroundPulmonary arterial hypertension (PAH) is a proliferative disease of the pulmonary vasculature that preferentially affects women. Estrogens such as the metabolite 16α-hydroxyestrone (16αOHE) may contribute to PAH pathogenesis, and alterations in cellular energy metabolism associate with PAH. We hypothesized that 16αOHE promotes heritable PAH (HPAH) via microRNA-29 (miR-29) family upregulation and that antagonism of miR-29 would attenuate pulmonary hypertension in transgenic mouse models of Bmpr2 mutation. METHODS AND
resultsMicroRNA array profiling of human lung tissue found elevation of microRNAs associated with energy metabolism, including the miR-29 family, among HPAH patients. miR-29 expression was 2-fold higher in Bmpr2 mutant mice lungs at baseline compared with controls and 4 to 8-fold higher in Bmpr2 mice exposed to 16αOHE 1.25 μg/h for 4 weeks. Blot analyses of Bmpr2 mouse lung protein showed significant reductions in peroxisome proliferator-activated receptor-γ and CD36 in those mice exposed to 16αOHE and protein derived from HPAH lungs compared with controls. Bmpr2 mice treated with anti-miR-29 (20-mg/kg injections for 6 weeks) had improvements in hemodynamic profile, histology, and markers of dysregulated energy metabolism compared with controls. Pulmonary artery smooth muscle cells derived from Bmpr2 murine lungs demonstrated mitochondrial abnormalities, which improved with anti-miR-29 transfection in vitro; endothelial-like cells derived from HPAH patient induced pluripotent stem cell lines were similar and improved with anti-miR-29 treatment.
conclusions16αOHE promotes the development of HPAH via upregulation of miR-29, which alters molecular and functional indexes of energy metabolism. Antagonism of miR-29 improves in vivo and in vitro features of HPAH and reveals a possible novel therapeutic target.
Indexed as
AnimalsBone Morphogenetic Protein Receptors, Type IICellular MicroenvironmentFemaleHumansHydroxyestronesHypertension, PulmonaryMaleMiceMice, TransgenicMicroRNAs16-hydroxyestroneBMPR2 protein, humanBone Morphogenetic Protein Receptors, Type IIHydroxyestronesMicroRNAsMIRN29a microRNA, humanestrogenshypertension, pulmonarymetabolismmicroRNAsmodels, animal
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