Peroxisome Proliferator-Activated Receptor γ Regulates the V-Ets Avian Erythroblastosis Virus E26 Oncogene Homolog 1/microRNA-27a Axis to Reduce Endothelin-1 and Endothelial Dysfunction in the Sickle Cell Mouse Lung
Peroxisome Proliferator-Activated Receptor γ Regulates the V-Ets Avian Erythroblastosis Virus E26 Oncogene Homolog 1/microRNA-27a Axis to Reduce Endothelin-1 and Endothelial Dysfunction in the Sickle Cell Mouse Lung
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DOI：
10.1165/rcmb.2016-0166oc
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发表时间：
2017-01-01
影响因子：
6.4
通讯作者：
Hart, C. Michael
中科院分区：
文献类型：
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作者：
Kang, Bum-Yong;Park, Kathy;Hart, C. Michael
肺动脉高压（PH）是镰状细胞病（SCD）的严重并发症，可导致显著的发病率和死亡率。虽然最近的研究确定，溶血过程中释放氯化血红素触发SCD的内皮功能障碍，SCD-PH的发病机制仍然不完全确定。本研究检测了过氧化物酶体增殖物激活受体γ（PPAR γ）在SCD-PH和内皮功能障碍中的调节作用。在Townes人源化镰状细胞（SS）和同窝对照（AA）小鼠中研究PH和右心室肥大。在平行研究中，SS或AA小鼠用10 mg/kg/天的PPAR γ激动剂罗格列酮（RSG）或溶剂灌胃10天。在体外，人肺动脉内皮细胞（HPAECs）与车辆或氯化血红素处理72小时，并选择HPAECs与RSG处理。SS小鼠发生PH和右心室肥大，与肺中PPAR γ水平降低和microRNA-27 a（miR-27 a）、v-ets禽成红细胞增多症病毒E26癌基因同源物1（ETS 1）、内皮素-1（ET-1）和内皮功能障碍标志物（血小板/内皮细胞粘附分子1和E选择素）水平升高相关。用氯化血红素处理的HPAEC具有增加的ETS 1、miR-27 a、ET-1和内皮功能障碍，以及降低的PPAR γ水平。这些紊乱通过ETS 1敲低、miR-27 a抑制或PPAR γ过表达而减弱。在SS小鼠肺或氯化血红素处理的HPAEC中，RSG对PPAR γ的激活减弱了PPAR γ的减少和miR-27 a、ET-1和内皮功能障碍标志物的增加。在SCD-PH发病机制中，ETS 1刺激miR-27 a水平增加，从而降低PPARg并增加ET-1和内皮功能障碍。PPAR γ激活减弱SCD相关信号紊乱，提示一种新的治疗方法，以减轻SCD-PH发病机制。
Pulmonary hypertension (PH), a serious complication of sickle cell disease (SCD), causes significant morbidity and mortality. Although a recent study determined that hemin release during hemolysis triggers endothelial dysfunction in SCD, the pathogenesis of SCD-PH remains incompletely defined. This study examines peroxisome proliferator-activated receptor gamma (PPAR gamma) regulation in SCD-PH and endothelial dysfunction. PH and right ventricular hypertrophy were studied in Townes humanized sickle cell (SS) and littermate control (AA) mice. In parallel studies, SS or AA mice were gavaged with the PPAR gamma agonist, rosiglitazone (RSG), 10mg/kg/day, or vehicle for 10 days. In vitro, human pulmonary artery endothelial cells (HPAECs) were treated with vehicle or hemin for 72 hours, and selected HPAECs were treated with RSG. SS mice developed PH and right ventricular hypertrophy associated with reduced lung levels of PPAR gamma and increased levels of microRNA-27a (miR-27a), v-ets avian erythroblastosis virus E26 oncogene homolog 1 (ETS1), endothelin-1 (ET-1), and markers of endothelial dysfunction (platelet/endothelial cell adhesion molecule 1 and E selectin). HPAECs treated with hemin had increased ETS1, miR-27a, ET-1, and endothelial dysfunction and decreased PPAR gamma levels. These derangements were attenuated by ETS1 knockdown, inhibition of miR-27a, or PPAR gamma overexpression. In SS mouse lung or in hemin-treated HPAECs, activation of PPAR gamma with RSG attenuated reductions in PPAR gamma and increases in miR-27a, ET-1, and markers of endothelial dysfunction. In SCD-PH pathogenesis, ETS1 stimulates increases in miR-27a levels that reduce PPARg and increase ET-1 and endothelial dysfunction. PPAR gamma activation attenuated SCD-associated signaling derangements, suggesting a novel therapeutic approach to attenuate SCD-PH pathogenesis.