Apelin改善RUPP大鼠模型的妊娠结局
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摘要
目的:观察apelin(APLN)处理RUPP(reduced uterine perfusion pressure)大鼠模型的临床表现和妊娠结局。方法:建立SD大鼠RUPP模型,孕14 d时随机分为4组:正常孕鼠组(n=6)、RUPP孕鼠(子痫前期,PE)组(n=7)、APLN组(n=7)和PE+APLN组(n=8)。APLN组及PE+APLN组的孕鼠皮下注射apelin-13。观察孕鼠血压、胎盘形态、胎儿存活及体重变化,检测孕鼠血清血管内皮生长因子A(VEGF-A)、可溶性fms样酪氨酸激酶1(sFlt-1)、总抗氧化能力(T-AOC)及丙二醛(MDA)水平的变化。结果:Apelin降低了PE+APLN组孕鼠的氧化应激状态,改善了血流动力学参数、胚胎存活率及胎盘胎体重量。结论:本实验为子痫前期的预防和治疗提供了新的药物研发依据。
AIM: By establishing RUPP (reduced uterine perfusion pressure) rat model,this study investigated whether apelin administration improves the clinical manifestations and pregnancy outcomes of preeclampsia (PE).METHODS: Sprague-Dawley (SD) rats at gestational age of 14 d were randomly divided into 4 groups: normal pregnant group (n = 6),pregnant RUPP (PE) group (n = 7),APLN group (n = 7) and PE + APLN group (n = 8). The rats in APLN group and PE + APLN group received subcutaneous injection of apelin-13. The blood pressure,placental and fetal weight,and the serum levels of vascular endothelial growth factor A (VEGF-A),soluble fms-like tyrosine kinase-1 (sFlt-1),total antioxidant capacity (T-AOC) and malondialdehyele (MDA) were observed. RESULTS: Apelin reduced oxidative stress state in PE + APLN group,and improved the hemodynamic parameters,embryo survival rate,placental weight and fetal weight. CONCLUSION: This study provides the evidence in new drug research and development for the prevention and treatment of preeclampsia.
AIM: By establishing RUPP (reduced uterine perfusion pressure) rat model,this study investigated whether apelin administration improves the clinical manifestations and pregnancy outcomes of preeclampsia (PE).METHODS: Sprague-Dawley (SD) rats at gestational age of 14 d were randomly divided into 4 groups: normal pregnant group (n = 6),pregnant RUPP (PE) group (n = 7),APLN group (n = 7) and PE + APLN group (n = 8). The rats in APLN group and PE + APLN group received subcutaneous injection of apelin-13. The blood pressure,placental and fetal weight,and the serum levels of vascular endothelial growth factor A (VEGF-A),soluble fms-like tyrosine kinase-1 (sFlt-1),total antioxidant capacity (T-AOC) and malondialdehyele (MDA) were observed. RESULTS: Apelin reduced oxidative stress state in PE + APLN group,and improved the hemodynamic parameters,embryo survival rate,placental weight and fetal weight. CONCLUSION: This study provides the evidence in new drug research and development for the prevention and treatment of preeclampsia.
引文
[1]Li J,La Marca B,Reckelhoff JF,et al.A model of preeclampsia in rats:the reduced uterine perfusion pressure(RUPP)model[J].Am J Physiol Heart Circ Physiol,2012,303(1):H1-H8.
[2]Alexander BT,Kassab SE,Miller MT,et al.Reduced uterine perfusion pressure during pregnancy in the rat is associated with increases in arterial pressure and changes in renal nitric oxide[J].Hypertension,2001,37(4):1191-1195.
[3]Herraiz S,Pellicer B,Serra V,et al.Sildenafil citrate improves perinatal outcome in fetuses from pre-eclamptic rats[J].BJOG,2012,119(11):1394-1402.
[4]Eric MG,Marietta A,Kathy C,et al.Induction of heme oxygenase-1 attenuates s Flt-1-induced hypertension in pregnant rats[J].Am J Physiol Regul Integr Comp Physiol,2011,301(5):R1495-R1500.
[5]Bauer AJ,Banek CT,Needham K,et al.Pravastatin attenuates hypertension,oxidative stress,and angiogenic imbalance in rat model of placental ischemia-induced hypertension[J].Hypertension,2013,61(5):1103-1110.
[6]Charles CJ,Rademaker MT,Richards AM.Apelin-13 induces a biphasic haemodynamic response and hormonal activation in normal conscious sheep[J].J Endocrinol,2006,189(3):701-710.
[7]Lee DK,Cheng R,Nguyen T,et al.Characterization of apelin,the ligand for the APJ receptor[J].J Neurochem,2000,74(1):34-41.
[8]Habata Y,Fujii R,Hosoya M,et al.Apelin,the natural ligand of the orphan receptor APJ,is abundantly secreted in the colostrum[J].Biochim Biophys Acta,1999,1452(1):25-35.
[9]Simpkin JC,Yellon DM,Davidson SM,et al.Apelin-13and apelin-36 exhibit direct cardioprotective activity against ischemia-reperfusion injury[J].Basic Res Cardiol,2007,102(6):518-528.
[10]Granger JP,La Marca BB,Cockrell K,et al.Reduced uterine perfusion pressure(RUPP)model for studying cardiovascular-renal dysfunction in response to placental ischemia[J].Methods Mol Med,2006,122:383-392.
[11]Yamaleyeva LM,Chappell MC,Brosnihan KB,et al.Downregulation of apelin in the human placental chorionic villi from preeclamptic pregnancies[J].Am J Physiol Endocrinol Metab,2015,309(10):E852-E860.
[12]Inuzuka H,Nishizawa H,Inagaki A,et al.Decreased expression of apelin in placentas from severe pre-eclampsia patients[J].Hypertens Pregnancy,2013,32(4):410-421.
[13]Mayeur S,Wattez JS,Lukaszewski MA,et al.Apelin controls fetal and neonatal glucose homeostasis and is altered by maternal undernutrition[J].Diabetes,2016,65(3):554-560.
[14]Pang H,Han B,Yu T,et al.Effect of apelin on the cardiac hemodynamics in hypertensive rats with heart[J].Int J Mol Med,2014,34(3):756-764.
[15]Kim J.Apelin-APJ signaling:a potential therapeutic target for pulmonary arterial hypertension[J].Mol Cells,2014,37(3):196-201.
[16]Hiroyasu K,Hisamichi N,Nobuyuki T.Apelin induces enlarged and nonleaky blood vessels for functional recovery from ischemia[J].Blood,2010,115(15):3166-3174.
[17]Garcia-Benavides L,Guzman-Sanchez A,Hernandez-Mora FJ,et al.Total antioxidant capacity in patients with pregnancy induced hypertension:its relation to maternal and/or perinatal complications[J].Pregnancy Hypertens,2012,2(3):282-283.
[18]Conde-Agudelo A,Romero R,Kusanovic JP,et al.Supplementation with vitamins C and E during pregnancy for the prevention of preeclampsia and other adverse maternal and perinatal outcomes:a systematic review and metaanalysis[J].Am J Obstet Gynecol,2011,204(6):503.e1-503.e12.
[2]Alexander BT,Kassab SE,Miller MT,et al.Reduced uterine perfusion pressure during pregnancy in the rat is associated with increases in arterial pressure and changes in renal nitric oxide[J].Hypertension,2001,37(4):1191-1195.
[3]Herraiz S,Pellicer B,Serra V,et al.Sildenafil citrate improves perinatal outcome in fetuses from pre-eclamptic rats[J].BJOG,2012,119(11):1394-1402.
[4]Eric MG,Marietta A,Kathy C,et al.Induction of heme oxygenase-1 attenuates s Flt-1-induced hypertension in pregnant rats[J].Am J Physiol Regul Integr Comp Physiol,2011,301(5):R1495-R1500.
[5]Bauer AJ,Banek CT,Needham K,et al.Pravastatin attenuates hypertension,oxidative stress,and angiogenic imbalance in rat model of placental ischemia-induced hypertension[J].Hypertension,2013,61(5):1103-1110.
[6]Charles CJ,Rademaker MT,Richards AM.Apelin-13 induces a biphasic haemodynamic response and hormonal activation in normal conscious sheep[J].J Endocrinol,2006,189(3):701-710.
[7]Lee DK,Cheng R,Nguyen T,et al.Characterization of apelin,the ligand for the APJ receptor[J].J Neurochem,2000,74(1):34-41.
[8]Habata Y,Fujii R,Hosoya M,et al.Apelin,the natural ligand of the orphan receptor APJ,is abundantly secreted in the colostrum[J].Biochim Biophys Acta,1999,1452(1):25-35.
[9]Simpkin JC,Yellon DM,Davidson SM,et al.Apelin-13and apelin-36 exhibit direct cardioprotective activity against ischemia-reperfusion injury[J].Basic Res Cardiol,2007,102(6):518-528.
[10]Granger JP,La Marca BB,Cockrell K,et al.Reduced uterine perfusion pressure(RUPP)model for studying cardiovascular-renal dysfunction in response to placental ischemia[J].Methods Mol Med,2006,122:383-392.
[11]Yamaleyeva LM,Chappell MC,Brosnihan KB,et al.Downregulation of apelin in the human placental chorionic villi from preeclamptic pregnancies[J].Am J Physiol Endocrinol Metab,2015,309(10):E852-E860.
[12]Inuzuka H,Nishizawa H,Inagaki A,et al.Decreased expression of apelin in placentas from severe pre-eclampsia patients[J].Hypertens Pregnancy,2013,32(4):410-421.
[13]Mayeur S,Wattez JS,Lukaszewski MA,et al.Apelin controls fetal and neonatal glucose homeostasis and is altered by maternal undernutrition[J].Diabetes,2016,65(3):554-560.
[14]Pang H,Han B,Yu T,et al.Effect of apelin on the cardiac hemodynamics in hypertensive rats with heart[J].Int J Mol Med,2014,34(3):756-764.
[15]Kim J.Apelin-APJ signaling:a potential therapeutic target for pulmonary arterial hypertension[J].Mol Cells,2014,37(3):196-201.
[16]Hiroyasu K,Hisamichi N,Nobuyuki T.Apelin induces enlarged and nonleaky blood vessels for functional recovery from ischemia[J].Blood,2010,115(15):3166-3174.
[17]Garcia-Benavides L,Guzman-Sanchez A,Hernandez-Mora FJ,et al.Total antioxidant capacity in patients with pregnancy induced hypertension:its relation to maternal and/or perinatal complications[J].Pregnancy Hypertens,2012,2(3):282-283.
[18]Conde-Agudelo A,Romero R,Kusanovic JP,et al.Supplementation with vitamins C and E during pregnancy for the prevention of preeclampsia and other adverse maternal and perinatal outcomes:a systematic review and metaanalysis[J].Am J Obstet Gynecol,2011,204(6):503.e1-503.e12.