Chaudhry Abubakr, Carthan Kristal A, Kang Bum-Yong, Calvert John, Sutliff Roy L, Michael Hart C
Division of Pulmonary, Allergy, Critical Care, and Sleep Medicine, Department of Medicine, Atlanta Veterans Affairs Medical Center and Emory University, Atlanta, GA, USA.
Department of Surgery, Emory University, Atlanta, GA, USA.
Pulm Circ. 2017 Mar 13;7(1):98-107. doi: 10.1086/689749. eCollection 2017 Mar.
Chronic hypoxia-induced pulmonary hypertension (PH) is characterized by increased pressure and resistance in the pulmonary vasculature and hypertrophy of the right ventricle (RV). The transcription factors, nuclear factor activated T-cells (NFAT), and nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB/p65) contribute to RV hypertrophy (RVH). Because peroxisome proliferator-activated receptor gamma (PPARγ) activation attenuates hypoxia-induced PH and RVH, we hypothesized that PPARγ inhibits activation of RV hypertrophic transcriptional signaling mechanisms. C57BL/6J mice were exposed to normoxia (21% O) or hypoxia (10% O) for 21 days. During the final 10 days of exposure, selected mice were treated with the PPARγ ligand, pioglitazone. RV systolic pressure (RVSP) and RVH were measured, and NFATc2 and NF-kB/p65 protein levels were measured in RV and LV nuclear and cytosolic fractions. Cardiomyocyte hypertrophy was assessed with wheatgerm agglutinin staining. NFAT activation was also examined with luciferase reporter mice and analysis of protein levels of selected transcriptional targets. Chronic-hypoxia increased: (1) RVH, RVSP, and RV cardiomyocyte hypertrophy; (2) NFATc2 and NF-κB activation in RV nuclear homogenates; (3) RV and LV NFAT luciferase activity; and (4) RV protein levels of brain natriuretic peptide (BNP) and β-myosin heavy chain (β-MyHC). Treatment with pioglitazone attenuated hypoxia-induced increases in both RV and LV NFAT luciferase activity. Chronic hypoxia caused sustained RV NFATc2 and NF-κB activation. Pioglitazone attenuated PH, RVH, cardiomyocyte hypertrophy, and activation of RV hypertrophic signaling and also attenuated LV NFAT activation. PPARγ favorably modulates signaling derangements in the heart as well as in the pulmonary vascular wall.
慢性缺氧诱导的肺动脉高压（PH）的特征是肺血管系统压力和阻力增加以及右心室（RV）肥厚。转录因子，活化T细胞核因子（NFAT）和活化B细胞核因子κ轻链增强子（NF-κB/p65）促成右心室肥厚（RVH）。由于过氧化物酶体增殖物激活受体γ（PPARγ）激活可减轻缺氧诱导的PH和RVH，我们推测PPARγ抑制右心室肥厚转录信号机制的激活。将C57BL/6J小鼠暴露于常氧（21% O）或缺氧（10% O）环境21天。在暴露的最后10天，给选定的小鼠用PPARγ配体吡格列酮治疗。测量右心室收缩压（RVSP）和RVH，并在右心室和左心室的核及胞质组分中测量NFATc2和NF-κB/p65蛋白水平。用麦胚凝集素染色评估心肌细胞肥大。还用荧光素酶报告基因小鼠和选定转录靶点的蛋白水平分析来检测NFAT激活。慢性缺氧增加：（1）RVH、RVSP和右心室心肌细胞肥大；（2）右心室核匀浆中NFATc2和NF-κB激活；（3）右心室和左心室NFAT荧光素酶活性；（4）右心室脑钠肽（BNP）和β-肌球蛋白重链（β-MyHC）的蛋白水平。吡格列酮治疗减弱了缺氧诱导的右心室和左心室NFAT荧光素酶活性增加。慢性缺氧导致右心室NFATc2和NF-κB持续激活。吡格列酮减轻了PH、RVH、心肌细胞肥大和右心室肥厚信号的激活，也减弱了左心室NFAT激活。PPARγ有利地调节心脏以及肺血管壁中的信号紊乱。
