Estrogen Metabolite 16α-Hydroxyestrone Exacerbates Bone Morphogenetic Protein Receptor Type II–Associated Pulmonary Arterial Hypertension Through MicroRNA-29–Mediated Modulation of Cellular Metabolism
Year: 2015
Type: article
Abstract: BACKGROUND: Pulmonary 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 RESULTS: MicroRNA 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. CONCLUSIONS: 16αOHE 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.
Source: Circulation
Authors: Xinping Chen, Megha Talati, Joshua P. Fessel, Anna R. Hemnes, Santhi Gladson, Jaketa French, Sheila Shay, Aaron Trammell, John A. Phillips, Rizwan Hamid, Joy D. Cogan, Elliott P. Dawson, Kristie E. Womble, Lora K. Hedges, Elizabeth G. Martinez, Lisa A. Wheeler, James E. Loyd, Susan J. Majka, James West, Eric D. Austin
Language: English
Subfield: Pulmonary and Respiratory Medicine
Field: Medicine
Domain: Health Sciences
Open Access status: green
Awards: Gender differences and endothelin responses in right ventricular afterload stress, Role of Lung MSC in Emphysema, Hormonal, Metabolic and Signaling Interactions in PAH, Variations in estrogen exposures may modify pulmonary arterial hypertension, Vanderbilt Center for Undiagnosed Diseases (VCUD), G5201076466, XFe96 Analyzer, Interventions Against the Molecular Etiology of BMPR2-induced PAH, Role of BMPR2 expression in HPAH; implications for novel therapeutic approaches, The Vanderbilt Institute for Clinical and Translational Research (VICTR), Interdisciplinary Training Program in Lung Research, Metabolic Reprogramming in Pulmonary Arterial Hypertension
OpenAlex ID: W2200344714