Estrogen Metabolite 16α-Hydroxyestrone Exacerbates Bone Morphogenetic Protein Receptor Type II–Associated Pulmonary Arterial Hypertension Through MicroRNA-29–Mediated Modulation of Cellular Metabolism

Abstract

Background Pulmonary arterial hypertension (PAH) is a proliferative disease of the pulmonary vasculature which preferentially affects females. 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 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 (miR) array profiling of human lung tissue found elevation of miRs 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 to controls, and 4 to 8-fold higher in Bmpr2 mice exposed to 16αOHE 1.25 μg/hr for 4 weeks. Blot analyses of Bmpr2 mouse lung protein showed significant reductions in PPARγ and CD36 in those mice exposed to 16αOHE, as well as from protein derived from HPAH lungs compared to controls. Bmpr2 mice treated with anti-miR-29 (α-miR29) (20mg/kg injections for 6 weeks) had improvements in hemodynamic profile, histology, and markers of dysregulated energy metabolism compared to controls. PASMCs derived from Bmpr2 murine lungs demonstrated mitochondrial abnormalities, which improved with α-miR29 transfection in vitro; endothelial-like cells derived from HPAH patient iPS cell lines were similar, and improved with α-miR29 treatment. Conclusions 16αOHE promotes the development of HPAH via upregulation of miR-29, which alters molecular and functional indices of energy metabolism. Antagonism of miR-29 improves in vivo and in vitro features of HPAH, and reveals a possible novel therapeutic target.

Inhibiting oestrogen signalling in pulmonary arterial hypertension: sex, drugs and research

“…The data presented are important in their support of the relevance of current and future clinical trials targeting interventions on oestrogen signalling pathways. In addition, the study further solidifies the potential link between oestrogens and metabolic alterations in PAH [13].…”

Pathobiology of pulmonary arterial hypertension: understanding the roads less travelled

“…However, a recent study by CHEN et al [72] has indicated a possible role for the miR-29 family. In this study, exposure to 16αOHE led to increased expression of miR-29 in BMPR2 mutant mice.…”

“…Instead, targeting the pathways downstream of E2, e.g. the miR-29 family, may provide a means of treating PAH without the need to modulate sex hormones directly [72].…”

Translational Advances in the Field of Pulmonary Hypertension.Translating MicroRNA Biology in Pulmonary Hypertension. It Will Take More Than “miR” Words

“…A sex-specific decrease in miR-96 was found to increase expression of the 5-hydroxytryptamine 1B receptor (42), thus predisposing to alteration of serotonin signaling and proliferative signals in the diseased pulmonary vasculature. Separately, a sex-specific interaction of miR-29 was described with estrogen metabolism (43), suggesting a molecular mechanism correlating female hormone signaling with the predisposition of PAH in women in the general population.…”