Xinping Chen1, Megha Talati1, Joshua P Fessel1, Anna R Hemnes1, Santhi Gladson1, Jaketa French1, Sheila Shay1, Aaron Trammell1, John A Phillips1, Rizwan Hamid1, Joy D Cogan1, Elliott P Dawson1, Kristie E Womble1, Lora K Hedges1, Elizabeth G Martinez1, Lisa A Wheeler1, James E Loyd1, Susan J Majka1, James West1, Eric D Austin2. 1. From 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.). 2. From 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.
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.
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 transgenicmouse 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 Bmpr2mice exposed to 16αOHE 1.25 μg/h for 4 weeks. Blot analyses of Bmpr2mouse 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. Bmpr2mice 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 Bmpr2murine 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.
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