雌激素代谢物16α-羟基雌酮通过微小RNA-29介导的细胞代谢调节加重II型骨形态发生蛋白受体相关的肺动脉高压。
Estrogen Metabolite 16α-Hydroxyestrone Exacerbates Bone Morphogenetic Protein Receptor Type II-Associated Pulmonary Arterial Hypertension Through MicroRNA-29-Mediated Modulation of Cellular Metabolism.
作者信息
Chen Xinping, Talati Megha, Fessel Joshua P, Hemnes Anna R, Gladson Santhi, French Jaketa, Shay Sheila, Trammell Aaron, Phillips John A, Hamid Rizwan, Cogan Joy D, Dawson Elliott P, Womble Kristie E, Hedges Lora K, Martinez Elizabeth G, Wheeler Lisa A, Loyd James E, Majka Susan J, West James, Austin Eric D
机构信息
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.).
出版信息
Circulation. 2016 Jan 5;133(1):82-97. doi: 10.1161/CIRCULATIONAHA.115.016133. Epub 2015 Oct 20.
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.
背景
肺动脉高压（PAH）是一种肺血管增殖性疾病，女性更易受影响。雌激素如代谢产物16α-羟基雌酮（16αOHE）可能参与PAH的发病机制，且细胞能量代谢改变与PAH相关。我们推测16αOHE通过上调微小RNA-29（miR-29）家族促进遗传性PAH（HPAH），并且在Bmpr2突变的转基因小鼠模型中，miR-29的拮抗作用将减轻肺动脉高压。
方法与结果
对人肺组织进行微小RNA阵列分析发现，HPAH患者中与能量代谢相关的微小RNA（包括miR-29家族）水平升高。与对照组相比，Bmpr2突变小鼠肺组织中miR-29的表达在基线时高2倍，在暴露于1.25μg/h 16αOHE 4周的Bmpr2小鼠中高4至8倍。对Bmpr2小鼠肺蛋白进行印迹分析显示，与对照组相比，暴露于16αOHE的小鼠以及来自HPAH肺组织的蛋白中，过氧化物酶体增殖物激活受体γ和CD36显著减少。与对照组相比，用抗miR-29治疗（20mg/kg注射6周）的Bmpr2小鼠在血流动力学特征、组织学和能量代谢失调标志物方面均有改善。源自Bmpr2小鼠肺组织的肺动脉平滑肌细胞表现出线粒体异常，体外抗miR-29转染后有所改善；源自HPAH患者诱导多能干细胞系的内皮样细胞也有类似情况，抗miR-29治疗后有所改善。
结论
16αOHE通过上调miR-29促进HPAH的发展，这改变了能量代谢的分子和功能指标。miR-29的拮抗作用改善了HPAH的体内和体外特征，并揭示了一个可能的新治疗靶点。
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