Objective This study aimed to investigate the effects of the peroxisome proliferator-activated receptorδ(PPARδ)agonist GW501516 on the proliferation of pulmonary artery smooth muscle cells(PASMCs)induced by hypoxia,...Objective This study aimed to investigate the effects of the peroxisome proliferator-activated receptorδ(PPARδ)agonist GW501516 on the proliferation of pulmonary artery smooth muscle cells(PASMCs)induced by hypoxia,in order to search for new drugs for the treatment and prevention of pulmonary vascular remodeling.Methods PASMCs were incubated with different concentrations of GW501516(10,30,100 nmol/L)under the hypoxic condition.The proliferation was determined by a CCK-8 assay.The cell cycle progression was analyzed by flow cytometry.The expression of PPARδ,S phase kinase-associated protein 2(Skp2),and cell cycle-dependent kinase inhibitor p27 was detected by Western blotting.Then PASMCs were treated with 100 nmol/L GW501516,100 nmol/L mammalian target of rapamycin(mTOR)inhibitor rapamycin and/or 2µmol/L mTOR activator MHY1485 to explore the molecular mechanisms by which GW501516 reduces the proliferation of PASMCs.Results The presented data demonstrated that hypoxia reduced the expression of PPARδin an oxygen concentration-and time-dependent manner,and GW501516 decreased the proliferation of PASMCs induced by hypoxia by blocking the progression through the G0/G1 to S phase of the cell cycle.In accordance with these findings,GW501516 downregulated Skp2 and upregulated p27 in hypoxia-exposed PASMCs.Further experiments showed that rapamycin had similar effects as GW501516 in inhibiting cell proliferation,arresting the cell cycle,regulating the expression of Skp2 and p27,and inactivating mTOR in hypoxia-exposed PASMCs.Moreover,MHY1485 reversed all the beneficial effects of GW501516 on hypoxia-stimulated PASMCs.Conclusion GW501516 inhibited the proliferation of PASMCs induced by hypoxia through blocking the mTOR/Skp2/p27 signaling pathway.展开更多
目的：研究过氧化物酶体增殖物激活受体（PPAR）-β/δ激动剂GW501516对老龄脓毒症大鼠心功能的影响。方法用盲肠结扎穿孔术（CLP）制备老龄大鼠脓毒症模型。50只老龄雄性SD大鼠，随机分为4组，分别为空白对照组（Con，n＝5）、假手术组...目的：研究过氧化物酶体增殖物激活受体（PPAR）-β/δ激动剂GW501516对老龄脓毒症大鼠心功能的影响。方法用盲肠结扎穿孔术（CLP）制备老龄大鼠脓毒症模型。50只老龄雄性SD大鼠，随机分为4组，分别为空白对照组（Con，n＝5）、假手术组（Sham组，n＝6）、CLP组，（n＝19）、CLP手术后应用GW501516液（0.05mg/100g）干预组（CLP＋GW组，n＝20）。记录术后48h内各组大鼠死亡情况，在术后48h利用超声心动图评价各组大鼠心率、每搏输出量、心指数、左室舒张末期内径、左室舒张末期容积等心功能指标。结果与单纯CLP组相比，CLP＋GW组组的老龄大鼠48h内死亡率降低（42.1%vs 15.0%，P＜0.05）。术后48h超声心动图显示，CLP＋GW组老龄大鼠与CLP组比较，心率明显降低[（318.55±16.65）vs（411.16±10.1）次/min，P＜0.01]；每搏输出量[（470.71±111.6） vs （171.47±39.85）ml/搏， P＜0.05]、心指数[（185.00±41.2） vs （102.05±19.94）ml/（min·mm2），P＜0.05]均较单纯CLP手术组显著升高；反映舒张功能的指标，左室舒张末期内径[（8.02±0.66） vs （5.65±0.45）mm，P＜0.05]和左室舒张末期容积[（5.13±1.00） vs （1.75±0.39）ml，P＜0.01]也较CLP组有明显增加。结论在早期给予老龄脓毒症大鼠GW501516进行液体复苏，可降低早期死亡率，明显改善心脏收缩与舒张功能，改善心脏做功。展开更多
基金supported by the National Natural Science Foundation of Hubei Province(No.2018CFC801).
文摘Objective This study aimed to investigate the effects of the peroxisome proliferator-activated receptorδ(PPARδ)agonist GW501516 on the proliferation of pulmonary artery smooth muscle cells(PASMCs)induced by hypoxia,in order to search for new drugs for the treatment and prevention of pulmonary vascular remodeling.Methods PASMCs were incubated with different concentrations of GW501516(10,30,100 nmol/L)under the hypoxic condition.The proliferation was determined by a CCK-8 assay.The cell cycle progression was analyzed by flow cytometry.The expression of PPARδ,S phase kinase-associated protein 2(Skp2),and cell cycle-dependent kinase inhibitor p27 was detected by Western blotting.Then PASMCs were treated with 100 nmol/L GW501516,100 nmol/L mammalian target of rapamycin(mTOR)inhibitor rapamycin and/or 2µmol/L mTOR activator MHY1485 to explore the molecular mechanisms by which GW501516 reduces the proliferation of PASMCs.Results The presented data demonstrated that hypoxia reduced the expression of PPARδin an oxygen concentration-and time-dependent manner,and GW501516 decreased the proliferation of PASMCs induced by hypoxia by blocking the progression through the G0/G1 to S phase of the cell cycle.In accordance with these findings,GW501516 downregulated Skp2 and upregulated p27 in hypoxia-exposed PASMCs.Further experiments showed that rapamycin had similar effects as GW501516 in inhibiting cell proliferation,arresting the cell cycle,regulating the expression of Skp2 and p27,and inactivating mTOR in hypoxia-exposed PASMCs.Moreover,MHY1485 reversed all the beneficial effects of GW501516 on hypoxia-stimulated PASMCs.Conclusion GW501516 inhibited the proliferation of PASMCs induced by hypoxia through blocking the mTOR/Skp2/p27 signaling pathway.
文摘目的：研究过氧化物酶体增殖物激活受体（PPAR）-β/δ激动剂GW501516对老龄脓毒症大鼠心功能的影响。方法用盲肠结扎穿孔术（CLP）制备老龄大鼠脓毒症模型。50只老龄雄性SD大鼠，随机分为4组，分别为空白对照组（Con，n＝5）、假手术组（Sham组，n＝6）、CLP组，（n＝19）、CLP手术后应用GW501516液（0.05mg/100g）干预组（CLP＋GW组，n＝20）。记录术后48h内各组大鼠死亡情况，在术后48h利用超声心动图评价各组大鼠心率、每搏输出量、心指数、左室舒张末期内径、左室舒张末期容积等心功能指标。结果与单纯CLP组相比，CLP＋GW组组的老龄大鼠48h内死亡率降低（42.1%vs 15.0%，P＜0.05）。术后48h超声心动图显示，CLP＋GW组老龄大鼠与CLP组比较，心率明显降低[（318.55±16.65）vs（411.16±10.1）次/min，P＜0.01]；每搏输出量[（470.71±111.6） vs （171.47±39.85）ml/搏， P＜0.05]、心指数[（185.00±41.2） vs （102.05±19.94）ml/（min·mm2），P＜0.05]均较单纯CLP手术组显著升高；反映舒张功能的指标，左室舒张末期内径[（8.02±0.66） vs （5.65±0.45）mm，P＜0.05]和左室舒张末期容积[（5.13±1.00） vs （1.75±0.39）ml，P＜0.01]也较CLP组有明显增加。结论在早期给予老龄脓毒症大鼠GW501516进行液体复苏，可降低早期死亡率，明显改善心脏收缩与舒张功能，改善心脏做功。
