子痫前期患者血清、胎盘follistatin-like 3和myostatin水平的变化及意义
|
摘要
背景：
子痫前期是发生于妊娠20周以后的妊娠期特有疾病,妊娠妇女中发病率约为7%-12%。临床表现为高血压、蛋白尿、水肿,严重者可出现抽搐、昏迷、心力衰竭、胎盘早剥、弥漫性血管内凝血和HELLP综合征(hemolysis, elevated serum level of liver enzymes, and low platelets),甚至死亡,严重危害母婴健康,是孕产妇和围生儿病率及死亡率的主要原因。
子痫前期的发病机制尚未阐明。目前,已经证实许多转化生长因子β(transforming growth factor-β, TGF-β)超家族的成员及其相关结合蛋白与子痫前期的发生、发展有关,activin信号通路——activin A以及相关蛋白,包括inhibin A、follistatin、follistatin-like 3等就是其中的热点。Activin A和inhibin A均是隶属于TGF-β超家族的糖蛋白,而follistatin则是TGF-β超家族成员的结合蛋白,能以高亲和力结合activin并拮抗其生理功能。TGF-β超家族成员及其相关蛋白在细胞的生长与分化、胚胎发育的调控以及维持成年动物内环境的稳定等方面均发挥着重要作用。大量研究证实在子痫前期孕妇外周血中activin A和inhibin A的浓度较正常妊娠对照组妇女显著增高,而follistatin的浓度则轻度升高或无显著变化。
Follistatin-like 3(FSTL3)又称为FLRG (Follistatin related-gene),是TGF-β超家族成员的一个结合蛋白,能够与TGF-β超家族的myostatin、activin、骨形成蛋白(bone morphogenetic protein, BMPs)、GDF-11等多个成员特异性的结合,抑制Smad介导的细胞内信号转导,进而抑制TGF-β超家族成员的生物学功能。Follistatin-like 3在胎盘、成熟的睾丸、心脏和胰腺组织中显著高表达。
Myostatin(MSTN)也被称为肌肉生长抑制素,是TGF-p超家族的一个新成员,由于与其他TGF-β超家族成员的同源性很低,又被称为生长分化因子-8(Growth and differential factor-8,GDF-8)。Myostatin的主要生物学功能是对骨骼肌细胞生长的负调控作用,同时也参与蛋白质、脂肪和糖代谢的调节。Myostatin主要在哺乳动物的骨骼肌中表达,在脂肪组织、胎盘组织和滋养细胞中也有一定的分布。目前发现,myostatin前肽、follistatin (FST)、follistatin-like 3、activin receptorⅡB (ACTRⅡB)拮抗剂和myostatin抗体均可抑制myostatin的功能。
有学者通过ELISA、实时荧光定量PCR、Western Blotting和免疫组化证实,与正常妊娠孕妇相比,子痫前期孕妇胎盘中follistatin-like 3的mRNA、蛋白的水平以及外周血中的follistatin-like 3的浓度均显著增加。但是目前关于子痫前期孕妇血清及胎盘myostatin水平的变化还是未知,子痫前期患者妊娠中期血follistatin-like 3和myostatin的变化也未见报道。
目的：
测定子痫前期患者和正常妊娠孕妇外周血、胎盘组织follistatin-like 3和myostatin的水平,以及发生子痫前期的患者及正常对照组孕妇妊娠中期血清follistatin-like 3和myostatin的水平,并观察妊娠中期血清follistatin-like 3和myostatin水平的变化与子痫前期的关系,探讨follistatin-like 3和myostatin子痫前期发生、发展中的作用。
方法：
研究分为三个部分。(一)采用ELISA测定子痫前期患者(40例)和正常妊娠妇女(40例)血清中follistatin-like 3和myostatin的浓度；(二)采用real-time PCR和Western Blotting分别测定子痫前期患者(40例)和正常妊娠妇女(40例)胎盘follistatin-like 3和myostatin的mRNA和蛋白表达；(三)采用ELISA测定发生子痫前期的病人(40例)和正常妊娠妇女(40例)妊娠中期的血清follistatin-like 3和myostatin的浓度。
结果：
子痫前期患者血清follistatin-like 3和myostatin水平显著高于正常妊娠对照组,差异有显著性(P均<0.001)。子痫前期患者胎盘follistatin-like 3和myostatin的mRNA和蛋白水平均显著高于对照组,有统计学差异性(P均<0.001)。重度与轻度子痫前期患者相比,血清、胎盘follistatin-like 3和myostatin水平均无显著性差异(P均>0.05)。发生子痫前期的患者妊娠中期血清follistatin-like 3的浓度低于对照组,有显著的统计学差异性(P<0.001),与晚期follistatin-like 3血清水平的变化是不一致的；而妊娠中期myostatin的浓度较对照组相比,则有显著增高(P<0.001),与晚期myostatin血清水平的变化趋势一致。
结论：
子痫前期患者的血清、胎盘follistatin-like 3和myostatin的水平较对照组相比,均有显著增高；但发生子痫前期的患者妊娠中期血清follistatin-like 3的浓度较对照组相比,显著下降,子痫前期患者myostatin的浓度在妊娠中期较对照组显著增高；这些发现提示follistatin-like 3和myostatin以一种较为复杂的方式参与子痫前期的发生发展,妊娠早期血清follistatin-like 3和myostatin的测定可以作为早期预测和诊断子痫前期的一种潜在策略。
Background:
Preeclampsia is a pregnancy-specific disease that occurs after 20 weeks'gestation and complicates 7-12% of all pregnancies worldwide. Preeclampsia is characterized by onset of hypertension, proteinuria and edema; severe preeclampsia could lead to convulsions, coma, heart failure, placental abruption, disseminated intravascular coagulation and HELLP syndrome, even death. Preeclampsia is a leading cause of maternal, fetal and neonatal mortality.
Etiology and pathology of preeclampsia remain largely unknown, it is reported that several members of TGF-βsuperfamily and their binding proteins are related to preeclampsia. The activin pathway that contains activin A, inhibin A, follistatin, follistatin-like 3 is one of the hotspots in research field of etiology and pathology of preeclampsia. Activin and inhibin are glycoproteins belonging to the transforming growth factorβ(TGF-β) superfamily; follistatin is a binding protein for TGF-βsuperfamily members and regulates biological activity of its ligand. Several lines of evidence documented a wide range of biological roles for the activins and related proteins in cell growth and differentiation, in regulating embryonic development and in maintaining tissue homeostasis in adult animals. It has been well evidenced that the placental expression and maternal serum levels of activin A and inhibin A are elevated in preeclamptic women. However, the changes in circulating follistatin are controversial. Reports of unchanged and enhanced follistatin in maternal serum were also available.
Follistatin-like 3 (FSTL3), also named follistatin-related gene (FLRG), a new member of binding protein for TGF-βsuperfamily members (such as myo statin, activin A, BMPs, GDF-11), it could antagonize their biological function by inhibiting Smad protein mediated intracellular signalling. Follistatin-like 3 is highly expressed in mature testicle and placenta, heart, and pancreatic tissue.
Myostatin (MSTN), also called GDF-8, is a relatively new member of TGF-βsuperfamily. Its main biological function is negative regulation for skeletal muscle cell growth, simultaneously myostatin also participate in regulating protein, fat and sugar metabolism. Myostatin is mainly expressed in mammalian skeletal muscle, adipose tissues, placental tissues and trophoblast. It is reported that myostatin propetide, follistatin, follistatin-like 3, ACTRⅡB antagonists and myostatin antibody could inhibit its function.
It was recently reported that placental expression of follistatin-like 3 at messenger RNA and protein and maternal serum concentration of follistatin-like 3 were significantly elevated in preeclampsia compared with normal pregnancy. However, the alterations of placental and circulating myostatin, the ligand of follistatin-like 3, in preeclampsia have not been investigated yet.
Objective:
To detect the serum and placentas levels of follistatin-like 3 and myostatin between preeclamptic and control women; to detect serum levels of follistatin-like 3 and myostatin in the second trimester of pregnancy in women who were destined to develop preeclampsia later; to analyze the alteration and role of follistatin-like 3 and myostatin in the occurrence and development of preeclampsia; to explore the possibility to predict and diagnose preeclampsia by testing the second-trimester serum levels of follistatin-like 3 and myostatin.
Methods:
Our study included three parts, in the first part we detected serum levels of follistatin-like 3 and myostatin between 40 preeclamptic and 40 normal pregnant women with ELISA; in the second part we detected mRNA and protein levels of the placentas in 40 preeclamptic and 40 normal pregnant women by real-time PCR and Western blotting respectively; in the third part we detected serum levels of follistatin-like 3 and myostatin in 15-20 weeks'gestation in 40 women who were destined to develop preeclampsia later and 40 normal pregnant women.
Results:
Compared with control group, serum and placental levels of folliatatin-like 3 and myostatin were significantly increased in preeclampsia group (P<0.001 for.both), there was no difference in the severe and mild preeclampsia (P>0.05 for both). Compared with control group, serum level of follistatin-like 3 was significantly lower in 15-20 weeks'gestation in preeclamptic women (P<0.001), however serum level of myostatin was significantly higher in 15-20 weeks'gestation in preeclamptic patients compared with control (P<0.001).
Conclusions:
The serum and placental expression of follistatin-like 3 and myostatin were elevated in preeclampsia, serum level of follistatin-like 3 in second trimester was decreased and myostatin was increased, it was suggested the complicated role of myostatin and its binding protein, follistatin-like 3, in preeclampsia, the serum level of follistatin-like 3 and myostatin might become potential markers of early prediction and diagnosis for preeclampsia
子痫前期是发生于妊娠20周以后的妊娠期特有疾病,妊娠妇女中发病率约为7%-12%。临床表现为高血压、蛋白尿、水肿,严重者可出现抽搐、昏迷、心力衰竭、胎盘早剥、弥漫性血管内凝血和HELLP综合征(hemolysis, elevated serum level of liver enzymes, and low platelets),甚至死亡,严重危害母婴健康,是孕产妇和围生儿病率及死亡率的主要原因。
子痫前期的发病机制尚未阐明。目前,已经证实许多转化生长因子β(transforming growth factor-β, TGF-β)超家族的成员及其相关结合蛋白与子痫前期的发生、发展有关,activin信号通路——activin A以及相关蛋白,包括inhibin A、follistatin、follistatin-like 3等就是其中的热点。Activin A和inhibin A均是隶属于TGF-β超家族的糖蛋白,而follistatin则是TGF-β超家族成员的结合蛋白,能以高亲和力结合activin并拮抗其生理功能。TGF-β超家族成员及其相关蛋白在细胞的生长与分化、胚胎发育的调控以及维持成年动物内环境的稳定等方面均发挥着重要作用。大量研究证实在子痫前期孕妇外周血中activin A和inhibin A的浓度较正常妊娠对照组妇女显著增高,而follistatin的浓度则轻度升高或无显著变化。
Follistatin-like 3(FSTL3)又称为FLRG (Follistatin related-gene),是TGF-β超家族成员的一个结合蛋白,能够与TGF-β超家族的myostatin、activin、骨形成蛋白(bone morphogenetic protein, BMPs)、GDF-11等多个成员特异性的结合,抑制Smad介导的细胞内信号转导,进而抑制TGF-β超家族成员的生物学功能。Follistatin-like 3在胎盘、成熟的睾丸、心脏和胰腺组织中显著高表达。
Myostatin(MSTN)也被称为肌肉生长抑制素,是TGF-p超家族的一个新成员,由于与其他TGF-β超家族成员的同源性很低,又被称为生长分化因子-8(Growth and differential factor-8,GDF-8)。Myostatin的主要生物学功能是对骨骼肌细胞生长的负调控作用,同时也参与蛋白质、脂肪和糖代谢的调节。Myostatin主要在哺乳动物的骨骼肌中表达,在脂肪组织、胎盘组织和滋养细胞中也有一定的分布。目前发现,myostatin前肽、follistatin (FST)、follistatin-like 3、activin receptorⅡB (ACTRⅡB)拮抗剂和myostatin抗体均可抑制myostatin的功能。
有学者通过ELISA、实时荧光定量PCR、Western Blotting和免疫组化证实,与正常妊娠孕妇相比,子痫前期孕妇胎盘中follistatin-like 3的mRNA、蛋白的水平以及外周血中的follistatin-like 3的浓度均显著增加。但是目前关于子痫前期孕妇血清及胎盘myostatin水平的变化还是未知,子痫前期患者妊娠中期血follistatin-like 3和myostatin的变化也未见报道。
目的：
测定子痫前期患者和正常妊娠孕妇外周血、胎盘组织follistatin-like 3和myostatin的水平,以及发生子痫前期的患者及正常对照组孕妇妊娠中期血清follistatin-like 3和myostatin的水平,并观察妊娠中期血清follistatin-like 3和myostatin水平的变化与子痫前期的关系,探讨follistatin-like 3和myostatin子痫前期发生、发展中的作用。
方法：
研究分为三个部分。(一)采用ELISA测定子痫前期患者(40例)和正常妊娠妇女(40例)血清中follistatin-like 3和myostatin的浓度；(二)采用real-time PCR和Western Blotting分别测定子痫前期患者(40例)和正常妊娠妇女(40例)胎盘follistatin-like 3和myostatin的mRNA和蛋白表达；(三)采用ELISA测定发生子痫前期的病人(40例)和正常妊娠妇女(40例)妊娠中期的血清follistatin-like 3和myostatin的浓度。
结果：
子痫前期患者血清follistatin-like 3和myostatin水平显著高于正常妊娠对照组,差异有显著性(P均<0.001)。子痫前期患者胎盘follistatin-like 3和myostatin的mRNA和蛋白水平均显著高于对照组,有统计学差异性(P均<0.001)。重度与轻度子痫前期患者相比,血清、胎盘follistatin-like 3和myostatin水平均无显著性差异(P均>0.05)。发生子痫前期的患者妊娠中期血清follistatin-like 3的浓度低于对照组,有显著的统计学差异性(P<0.001),与晚期follistatin-like 3血清水平的变化是不一致的；而妊娠中期myostatin的浓度较对照组相比,则有显著增高(P<0.001),与晚期myostatin血清水平的变化趋势一致。
结论：
子痫前期患者的血清、胎盘follistatin-like 3和myostatin的水平较对照组相比,均有显著增高；但发生子痫前期的患者妊娠中期血清follistatin-like 3的浓度较对照组相比,显著下降,子痫前期患者myostatin的浓度在妊娠中期较对照组显著增高；这些发现提示follistatin-like 3和myostatin以一种较为复杂的方式参与子痫前期的发生发展,妊娠早期血清follistatin-like 3和myostatin的测定可以作为早期预测和诊断子痫前期的一种潜在策略。
Background:
Preeclampsia is a pregnancy-specific disease that occurs after 20 weeks'gestation and complicates 7-12% of all pregnancies worldwide. Preeclampsia is characterized by onset of hypertension, proteinuria and edema; severe preeclampsia could lead to convulsions, coma, heart failure, placental abruption, disseminated intravascular coagulation and HELLP syndrome, even death. Preeclampsia is a leading cause of maternal, fetal and neonatal mortality.
Etiology and pathology of preeclampsia remain largely unknown, it is reported that several members of TGF-βsuperfamily and their binding proteins are related to preeclampsia. The activin pathway that contains activin A, inhibin A, follistatin, follistatin-like 3 is one of the hotspots in research field of etiology and pathology of preeclampsia. Activin and inhibin are glycoproteins belonging to the transforming growth factorβ(TGF-β) superfamily; follistatin is a binding protein for TGF-βsuperfamily members and regulates biological activity of its ligand. Several lines of evidence documented a wide range of biological roles for the activins and related proteins in cell growth and differentiation, in regulating embryonic development and in maintaining tissue homeostasis in adult animals. It has been well evidenced that the placental expression and maternal serum levels of activin A and inhibin A are elevated in preeclamptic women. However, the changes in circulating follistatin are controversial. Reports of unchanged and enhanced follistatin in maternal serum were also available.
Follistatin-like 3 (FSTL3), also named follistatin-related gene (FLRG), a new member of binding protein for TGF-βsuperfamily members (such as myo statin, activin A, BMPs, GDF-11), it could antagonize their biological function by inhibiting Smad protein mediated intracellular signalling. Follistatin-like 3 is highly expressed in mature testicle and placenta, heart, and pancreatic tissue.
Myostatin (MSTN), also called GDF-8, is a relatively new member of TGF-βsuperfamily. Its main biological function is negative regulation for skeletal muscle cell growth, simultaneously myostatin also participate in regulating protein, fat and sugar metabolism. Myostatin is mainly expressed in mammalian skeletal muscle, adipose tissues, placental tissues and trophoblast. It is reported that myostatin propetide, follistatin, follistatin-like 3, ACTRⅡB antagonists and myostatin antibody could inhibit its function.
It was recently reported that placental expression of follistatin-like 3 at messenger RNA and protein and maternal serum concentration of follistatin-like 3 were significantly elevated in preeclampsia compared with normal pregnancy. However, the alterations of placental and circulating myostatin, the ligand of follistatin-like 3, in preeclampsia have not been investigated yet.
Objective:
To detect the serum and placentas levels of follistatin-like 3 and myostatin between preeclamptic and control women; to detect serum levels of follistatin-like 3 and myostatin in the second trimester of pregnancy in women who were destined to develop preeclampsia later; to analyze the alteration and role of follistatin-like 3 and myostatin in the occurrence and development of preeclampsia; to explore the possibility to predict and diagnose preeclampsia by testing the second-trimester serum levels of follistatin-like 3 and myostatin.
Methods:
Our study included three parts, in the first part we detected serum levels of follistatin-like 3 and myostatin between 40 preeclamptic and 40 normal pregnant women with ELISA; in the second part we detected mRNA and protein levels of the placentas in 40 preeclamptic and 40 normal pregnant women by real-time PCR and Western blotting respectively; in the third part we detected serum levels of follistatin-like 3 and myostatin in 15-20 weeks'gestation in 40 women who were destined to develop preeclampsia later and 40 normal pregnant women.
Results:
Compared with control group, serum and placental levels of folliatatin-like 3 and myostatin were significantly increased in preeclampsia group (P<0.001 for.both), there was no difference in the severe and mild preeclampsia (P>0.05 for both). Compared with control group, serum level of follistatin-like 3 was significantly lower in 15-20 weeks'gestation in preeclamptic women (P<0.001), however serum level of myostatin was significantly higher in 15-20 weeks'gestation in preeclamptic patients compared with control (P<0.001).
Conclusions:
The serum and placental expression of follistatin-like 3 and myostatin were elevated in preeclampsia, serum level of follistatin-like 3 in second trimester was decreased and myostatin was increased, it was suggested the complicated role of myostatin and its binding protein, follistatin-like 3, in preeclampsia, the serum level of follistatin-like 3 and myostatin might become potential markers of early prediction and diagnosis for preeclampsia
引文
[1]Sibai B, Dekker G, Kupferminc M. Pre-eclampisa. Lancet.2005;365,785-99.
[2]Roberts JM and Gammill HS. Preeclampsia:recent insights. Hypertension 2005; 46:1243-9.
[3]Bell MJ. A historical overview of preeclampsia-eclampsia. J Obstet Gynecol Neonatal Nurs 2010;39:510-8.
[4]Redman CW and Sargent IL. Latest advances in understanding preeclampsia. Science 2005;308:1592-4.
[5]Mutter WP, Karumanchi SA. Molecular mechanisms of preeclampsia. Microvasc Res 2008;75:1-8.
[6]Silver HM, Lambert-Messerlian GM, Reis FM, Diblasio AM, Petraglia F, Canick JA. Mechanism of increased maternal serum total activin a and inhibin a in preeclampsia. J Soc Gynecol Investig 2002;9:308-12.
[7]Casagrandi D, Bearfield C, Geary J, Redrman CW, Muttukrishna S. Inhibin, activin, follistatin, sctivin receptors and beta-glycan gene expression in the placental tissue of patients with preeclampsia. Mol Hum Reprod 2003; 9:199-203.
[8]Khalil A, Jauniaux E, Harrington K, Muttukrishna S. Placental production and maternal serum and urine levels of inhibin A and acivin A are modified by antihypertensive therapy in hypertensive disorders of pregnancy. Clin Endocrinol (Oxf)2009;70:924-31.
[9]Muttukrishna S, Knight PG, Groome NP, Redman CW, Ledger WL. Activin A and inhibin A as possible endocrine markers for pre-eclampsia. Lancet 1997; 349:1285-8.
[10]Yu J, Shixia CZ, Wu Y, Duan T. The study of inhibin A, activin A, placental growth factor and uterine artery Doppler pulsatility index to predict pre-eclampsia. Ultrasound Obstet Gynecol 2010;Aug 24. [Epub ahead of print].
[11]Reddy A, Suri S, Sargent IL, Redman CW, Muttukrishna S. Maternal circulating levels of activin A, inhibin A, sFlt-1 and endoglin at parturition in normal pregnancy and pre-eclampsia. Plos One 2009;4:e4553.
[12]Jones RL, Stoikos C, Findlay JK, Salamonsen LA. TGF-beta superfamily expression and actions in the endometrium and placenta. Reproduction 2006;132: 217-32.
[13]Peracoli MT, Menegon FT, Borges VT, de Araujo Costa RA, Thomazini-Santos IA, Peracoli JC. Platelet aggregation and TGF-beta(1) plasma levels in pregnant women with preeclampsia. J Reprod Immunol 2008;79:79-84.
[14]Keelan JA, Taylor R, Schellenberg JC, Groome NP, Mitchell MD, North RA. Serum activin A, inhibin A, and follistatin concentrations in preeclampsia or small for gestational age pregnancies. Obstet Gynecol 2002;99:267-74.
[15]D'Antona D, Reis FM, Benedetto C, Evans LW, Groome NP, de Kretser DM, et al. Increased maternal serum activin A but not follistatin levels in pregnant women with hypertensive disorders. J Endocrinol 2000;1651:157-62.
[16]Hayette S, Gadoux M, Martel S, Bertrand S, Tigaud I, Magaud JP, Rimokh R. FLRG (follistatin-related gene), a new target of chromosomal rearrangement in malignant blood disorders. Oncogene 1998;16:2949-54.
[17]Tortoriello DV, Sidis Y, Holtzman DA, Holmes WE, Schneyer AL. Human follistatin-related protein:a structural homologue of follistatin with nuclear localization. Endocrinology 2001;142:3426-34.
[18]McPherron AC, Lee S J. Double muscling in cattle due to mutations in the myostatin gene Proc Natl Acad Sci USA 1997; 94:12457-611.
[19]Ji S, Losinski RL, Cornelius SG, Frank GR, Willis GM, Gerrard DE, Depreux FF, Spurlock ME. Myostatin expression in porcine tissues:tissue specificity and developmental and postnatal regulation. Am J Physiol 1998; 275:R1265-73.
[20]Hill JJ, Davies MV, Pearson AA, Wang JH, Hewick RM, Wolfman NM, Qiu Y. The myostatin propeptide and the follistatin-related gene are inhibitory binding proteins of myostatin in normal serum. J Biol Chem 2002; 277:40735-41.
[21]Hill JJ, Qiu J, Hewick RM, Wolfman NM. Regulation of myostatin in vivo by growth and differentiation factor-associated serum protein-1:a novel protein with protease inhibitor and follistatin domains. Mol Endocrinol 2003; 17:1144-54.
[22]Biron-Shental T, Schaiff WT, Rimon E, Shim TL, Nelson DM, Sadovsky Y. Hypoxia enhance the expression of follistatin-like 3 in term human trophoblasts. Placenta 2008;29:51-7.
[23]McCarthy C, Cotter FE, McElwaine S, Twomey A, Mooney EE, Ryan F, Vaughan J. Altered gene expression patterns in intrauterine growth restriction:potential role of hypoxia. Am J Obstet Gynecol 2007;196:70.e1-6.
[24]Pryor-Koishi K, Nishizawa H, Kato T, Kogo H, Murakami T, Tsuchida K, Kurahashi H, Udagawa Y. Overproduction of the follistatin-related gene protein in the placenta and maternal serum of women with pre-eclampsia. BJOG 2007; 114:1128-37.
[25]丰有吉、沈铿.妇产科学[M].8版.北京：人民卫生出报社,2005：77-78.
[26]Petraglia F, Aguzzoli L, Gallinelli A, Florio P, Zonca M, Benedetto C, Woodruff K. Hypertension in pregnancy:changes in activin A maternal serum concentration. Placenta 1995; 16:447-54.
[27]Petraglia F, Vaughan J, Vale W. Inhibin and activin modulate the release of GnRH, hCG and progesterone from cultured human placental cells. PNAS 1989; 86: 5114-7.
[28]Tiemy EP, Giudice LC. Role of activin A as a mediator of in vitro endometrial stromal cell decidualization via the cyclic adenosine monophosphate pathway. Fertil Steril 2004; 81:899-903.
[29]Khalil A, Jauniaux E, Harrington K, et al. Placental production and maternal serum and urine levels of inhibin A and activin A are modified by antihypertensive therapy in hypertensive disorders of pregnancy. Clin Endocrinol (Oxf),20009,70:924-931.
[30]Bersinger NA, Smarason AK, Muttukrishna S, Groome NP, Redman CW. Women with preeclampsia have increased serum levels of pregnancy-associated palsma protein A (PAPP-A), inhibin A, activin A and soluble E-selectin. Hypertens Pregnancy 2003; 22(1):45-55.
[31]Lu D, Yang X, Wu Y, Wang H, Huang H, Dong M. Serum adiponetin, leptin and soluble leptin receptor in preeclampsia. Int J Gynaecol Obstet 2006; 95:121-6.
[32]Hendler I, Blackwell SC, Mehta SH, Whitty JE, Russell E, Sorokin Y, Cotton DB. The levels of leptin, adiponectin, and resistin in normal weight, overweight, and obese pregnant women with and without preeclampsia. Am J Obstet Gynecol 2005; 193:979-83.
[33]Henson MC and Castracane VD. Leptin in pregnancy:an update. Biol Reprod 2006;74:218-29.
[34]Adali E, Yildizhan R, Kolusari A, et al. Increased visfatin and leptin in pregnancies complicated by pre-eclampsia. J Matern Fetal Neonatal Med 2009; 22:873-9.
[35]Fasshauer M, Waldeyer T, Seeger J, et al. Serum levels of the adipokine visfatin are increased in pre-eclampsia. Clin Endocrinol (Oxf) 2008;69:69-73.
[36]Shangguan X, Liu F, Wang H, He J, Dong M. Alterations in serum adipocyte fatty acid binding protein and retinol binding protein-4 in normal pregnancy and preeclampsia. Clin Chim Acta 2009;407:58-61.
[37]Vaisbuch E, Romero R, Mazaki-Tovi S, et al. Retinol binding protein 4--a novel association with early-onset preeclampsia. J Perinat Med 2010; 38:129-39.
[38]Stepan H, Ebert T, Schrey S, et al. Preliminary report:Serum levels of retinol-binding protein 4 in preeclampsia. Metabolism 2009;58:275-7.
[39]Fasshauer M, Seeger J, Waldeyer T, et al. Serum levels of the adipokine adipocyte fatty acid-binding protein are increased in preeclampsia. Am J Hypertens 2008; 21:582-6.
[40]Cortelazzi D, Corbetta S, Ronzoni S, et al. Maternal and foetal resistin and adippnectin concentrations in normal and complicated pregnancies. Clin Endocrinol (Oxf) 2007;66:447-53.
[41]McPherron AC, Lee SJ. Suppression of body fat accumulation in myostatin-deficient mice. J Clin Invest 2002;109:595-601
[42]叶建伟.Myostatin对成肌细胞糖代谢的影响[D].中国协和医科大学；2006年
[43]Birdsall M, Ledger W, Groome N, Abdalla H, Muttukrishna S. Inhibin A and activin A in the first trimester of human pregnancy. J Clin Endocrinol Metab 1997; 82:1557-60.
[44]Muttukrishna S, George L, Fowler PA, Groome NP, Knight PG. Measurement of serum concentrations of inhibin-A (alpha-beta A dimer) during human pregnancy. Clin Endocrinol (Oxf) 1995;42:391-7.
[45]Muttukrishna S, North RA, Morri S, Schellenberg JC, Taylor RS, Asselin J, et al. Serum inhibin A and activin A are elevated prior to the onset of preeclampsia. Hum Reprod 2000; 15:1640-5
[46]Plevyak MP, Lambert-Messerliah GM, Farina A, Groome NP, Canick JA, Silver HM. Concentration of serum total activin A and inhibin A in preterm and term labor patients:a cross-sectional study. J Soc Gynecol Investig 2003;10:231-6.
[47]Muttukrishna S, Fowler PA, George L, Groome NP, Knight PG. Changes in peripheral serum levels of total activin A during the human menstrual cycle and pregnancy. J Clin Endocrinol Metab 1996; 81:3328-34.
[48]Sandra AF, Yvette PC, James FL, Arun J, W Allen H, Kirk PC. Altered global gene expression in first trimester placentas of women destined to develop preeclampsia. Placenta 2009;30:15-24
[1]Ji S, Losinski RL, Cornelius SG, et al. Myostatin expression in porcine tissues: tissue specificity and developmental and postnatal regulation [J]. Am J Physiol, 1998,275(4):1265-1273.
[2]Mendias, CL, Bakhurin KI, Faulkner JA. Tendons of myostatin-deficient mice are small, brittle, and hypocellular [J]. Proc Natl Acad Sci USA,2008,105(1): 388-393.
[3]Tortoriello DV, Sidis Y, Holtzman DA, et al. Human follistatin-related protein:a structural homologue of follistatin with nuclear localization [J]. Endocrinology, 2001,142(8):3426-3434.
[4]Hill JJ, Davies MV, Pearson AA, et al. The myostatin propeptide and the follistatin-related gene are inhibitory binding proteins of myostatin in normal serum [J]. J Biol Chem,2002,277(43):40735-40741.
[5]Hu S, Chen C, Sheng J, et al. Enhanced muscle growth by plasmid-mediated delivery of myostatin propeptide [J]. J Biomed Biotechnol,2010,2010:862591. Epub 2010 Mar 15.
[6]Zhao B, Wall RJ, Yang J. Transgenic expression of myostatin propetide prevents diet-induced obesity and insulin resistance [J]. Biochem Biophys Res Commun, 2006,337(1):248-255.
[7]Guo T, Jou W, Chanturiya T, et al. Myostatin inhibition in muscle, but not adipose tissue, decreases fat mass and improves insulin sensitivity [J]. Plos One,2009, 4(3):e4937.
[8]Wilkes JJ, Lloyd DJ, Gekakis N. Loss-of-function mutation in myostatin reduces tumor necrosis factor alpha production and protects liver against obesity-induced insulin resistance [J]. Diabetes,2009,58(5):1133-1143.
[9]Prakash A, Tuckerman E, Laird S, et al. A preliminary study comparing the endometrial expression of inhibin, activin and follistatin in women with a history of implantation failure after IVF treatment and a control group [J]. BJOG,2008, 115(4):532-537.
[10]Szabat M, Johnson JD, Piret JM. Reciprocal modulation of adult beta cell maturity by activin A and follistatin [J]. Diabetologia,2010,53 (8):1680-1689.
[11]Chen MJ, Chen HF, Chen SU, et al. The relationship between follistatin and chronic low-grade inflammation in women with poly cystic ovary syndrome [J]. Fertil Steril,2009,92(6):2041-2044.
[12]Haidet AM, Rizo L, Handy C, et al. Long-term enhancement of skeletal muscle and strength by single gene administration of myostatin inhibitors [J]. Proc Natl Acad Sci USA,2008,105(11):4318-4322.
[13]Medina J, Yamada S, Kojima I. Identification of differentially expressed genes during proliferative response of the liver induced by follistatin [J]. Endocr J,2009, 56(9):1067-1077.
[14]McCarthy C, Cotter FE, McElwaine S, et al. Altered gene expression patterns in intrauterine growth restriction:potential role of hypoxia [J]. Am J Obstet Gynecol, 2007,196(1):70.e1-6.
[15]Pryor-Koishi K, Nishizawa H, Kato T, et al. Overproduction of the follistatin-related gene protein in the placenta and maternal serum of women with pre-eclampsia [J]. BJOG,2007,114(9):1128-1137.
[16]Torres PB, Florio P, Ferreia MC, et al. Deranged expression of follistatin and follistatin-like protein in women with ovarian endometriosis [J]. Fertil Steril, 2007,88(1):200-205.
[17]Mukherjec A, Sidis Y, Mahan A, et al. FSTL3 deletion reveals roles for TGF-beta family ligands in glucose and fat homeostasis in adults [J]. Proc Natl Acad Sci USA,2007,104(4):1348-1353.
[18]Thadhani R, Powe CE, Tjoa ML, et al. First-trimester follistatin-like-3 levels in pregnancies complicated by subsequent gestational diabetes mellitus [J]. Diabetes Care,2010,33(3):664-669.
[19]Razanajaona D, Joguet S, Ay AS, et al. Silencing of FLRG, an antagonist of activin, inhibits human breast tumor cell growth [J]. Cancer Res,2007,67(15): 7223-7229.
[20]Mukherjec A, Sidis Y, Mahan A, et al. FSTL3 deletion reveals roles for TGF-beta family ligands in glucose and fat homeostasis in adults [J]. Proc Natl Acad Sci USA,2007,104(4):1348-1353.
[2]Roberts JM and Gammill HS. Preeclampsia:recent insights. Hypertension 2005; 46:1243-9.
[3]Bell MJ. A historical overview of preeclampsia-eclampsia. J Obstet Gynecol Neonatal Nurs 2010;39:510-8.
[4]Redman CW and Sargent IL. Latest advances in understanding preeclampsia. Science 2005;308:1592-4.
[5]Mutter WP, Karumanchi SA. Molecular mechanisms of preeclampsia. Microvasc Res 2008;75:1-8.
[6]Silver HM, Lambert-Messerlian GM, Reis FM, Diblasio AM, Petraglia F, Canick JA. Mechanism of increased maternal serum total activin a and inhibin a in preeclampsia. J Soc Gynecol Investig 2002;9:308-12.
[7]Casagrandi D, Bearfield C, Geary J, Redrman CW, Muttukrishna S. Inhibin, activin, follistatin, sctivin receptors and beta-glycan gene expression in the placental tissue of patients with preeclampsia. Mol Hum Reprod 2003; 9:199-203.
[8]Khalil A, Jauniaux E, Harrington K, Muttukrishna S. Placental production and maternal serum and urine levels of inhibin A and acivin A are modified by antihypertensive therapy in hypertensive disorders of pregnancy. Clin Endocrinol (Oxf)2009;70:924-31.
[9]Muttukrishna S, Knight PG, Groome NP, Redman CW, Ledger WL. Activin A and inhibin A as possible endocrine markers for pre-eclampsia. Lancet 1997; 349:1285-8.
[10]Yu J, Shixia CZ, Wu Y, Duan T. The study of inhibin A, activin A, placental growth factor and uterine artery Doppler pulsatility index to predict pre-eclampsia. Ultrasound Obstet Gynecol 2010;Aug 24. [Epub ahead of print].
[11]Reddy A, Suri S, Sargent IL, Redman CW, Muttukrishna S. Maternal circulating levels of activin A, inhibin A, sFlt-1 and endoglin at parturition in normal pregnancy and pre-eclampsia. Plos One 2009;4:e4553.
[12]Jones RL, Stoikos C, Findlay JK, Salamonsen LA. TGF-beta superfamily expression and actions in the endometrium and placenta. Reproduction 2006;132: 217-32.
[13]Peracoli MT, Menegon FT, Borges VT, de Araujo Costa RA, Thomazini-Santos IA, Peracoli JC. Platelet aggregation and TGF-beta(1) plasma levels in pregnant women with preeclampsia. J Reprod Immunol 2008;79:79-84.
[14]Keelan JA, Taylor R, Schellenberg JC, Groome NP, Mitchell MD, North RA. Serum activin A, inhibin A, and follistatin concentrations in preeclampsia or small for gestational age pregnancies. Obstet Gynecol 2002;99:267-74.
[15]D'Antona D, Reis FM, Benedetto C, Evans LW, Groome NP, de Kretser DM, et al. Increased maternal serum activin A but not follistatin levels in pregnant women with hypertensive disorders. J Endocrinol 2000;1651:157-62.
[16]Hayette S, Gadoux M, Martel S, Bertrand S, Tigaud I, Magaud JP, Rimokh R. FLRG (follistatin-related gene), a new target of chromosomal rearrangement in malignant blood disorders. Oncogene 1998;16:2949-54.
[17]Tortoriello DV, Sidis Y, Holtzman DA, Holmes WE, Schneyer AL. Human follistatin-related protein:a structural homologue of follistatin with nuclear localization. Endocrinology 2001;142:3426-34.
[18]McPherron AC, Lee S J. Double muscling in cattle due to mutations in the myostatin gene Proc Natl Acad Sci USA 1997; 94:12457-611.
[19]Ji S, Losinski RL, Cornelius SG, Frank GR, Willis GM, Gerrard DE, Depreux FF, Spurlock ME. Myostatin expression in porcine tissues:tissue specificity and developmental and postnatal regulation. Am J Physiol 1998; 275:R1265-73.
[20]Hill JJ, Davies MV, Pearson AA, Wang JH, Hewick RM, Wolfman NM, Qiu Y. The myostatin propeptide and the follistatin-related gene are inhibitory binding proteins of myostatin in normal serum. J Biol Chem 2002; 277:40735-41.
[21]Hill JJ, Qiu J, Hewick RM, Wolfman NM. Regulation of myostatin in vivo by growth and differentiation factor-associated serum protein-1:a novel protein with protease inhibitor and follistatin domains. Mol Endocrinol 2003; 17:1144-54.
[22]Biron-Shental T, Schaiff WT, Rimon E, Shim TL, Nelson DM, Sadovsky Y. Hypoxia enhance the expression of follistatin-like 3 in term human trophoblasts. Placenta 2008;29:51-7.
[23]McCarthy C, Cotter FE, McElwaine S, Twomey A, Mooney EE, Ryan F, Vaughan J. Altered gene expression patterns in intrauterine growth restriction:potential role of hypoxia. Am J Obstet Gynecol 2007;196:70.e1-6.
[24]Pryor-Koishi K, Nishizawa H, Kato T, Kogo H, Murakami T, Tsuchida K, Kurahashi H, Udagawa Y. Overproduction of the follistatin-related gene protein in the placenta and maternal serum of women with pre-eclampsia. BJOG 2007; 114:1128-37.
[25]丰有吉、沈铿.妇产科学[M].8版.北京：人民卫生出报社,2005：77-78.
[26]Petraglia F, Aguzzoli L, Gallinelli A, Florio P, Zonca M, Benedetto C, Woodruff K. Hypertension in pregnancy:changes in activin A maternal serum concentration. Placenta 1995; 16:447-54.
[27]Petraglia F, Vaughan J, Vale W. Inhibin and activin modulate the release of GnRH, hCG and progesterone from cultured human placental cells. PNAS 1989; 86: 5114-7.
[28]Tiemy EP, Giudice LC. Role of activin A as a mediator of in vitro endometrial stromal cell decidualization via the cyclic adenosine monophosphate pathway. Fertil Steril 2004; 81:899-903.
[29]Khalil A, Jauniaux E, Harrington K, et al. Placental production and maternal serum and urine levels of inhibin A and activin A are modified by antihypertensive therapy in hypertensive disorders of pregnancy. Clin Endocrinol (Oxf),20009,70:924-931.
[30]Bersinger NA, Smarason AK, Muttukrishna S, Groome NP, Redman CW. Women with preeclampsia have increased serum levels of pregnancy-associated palsma protein A (PAPP-A), inhibin A, activin A and soluble E-selectin. Hypertens Pregnancy 2003; 22(1):45-55.
[31]Lu D, Yang X, Wu Y, Wang H, Huang H, Dong M. Serum adiponetin, leptin and soluble leptin receptor in preeclampsia. Int J Gynaecol Obstet 2006; 95:121-6.
[32]Hendler I, Blackwell SC, Mehta SH, Whitty JE, Russell E, Sorokin Y, Cotton DB. The levels of leptin, adiponectin, and resistin in normal weight, overweight, and obese pregnant women with and without preeclampsia. Am J Obstet Gynecol 2005; 193:979-83.
[33]Henson MC and Castracane VD. Leptin in pregnancy:an update. Biol Reprod 2006;74:218-29.
[34]Adali E, Yildizhan R, Kolusari A, et al. Increased visfatin and leptin in pregnancies complicated by pre-eclampsia. J Matern Fetal Neonatal Med 2009; 22:873-9.
[35]Fasshauer M, Waldeyer T, Seeger J, et al. Serum levels of the adipokine visfatin are increased in pre-eclampsia. Clin Endocrinol (Oxf) 2008;69:69-73.
[36]Shangguan X, Liu F, Wang H, He J, Dong M. Alterations in serum adipocyte fatty acid binding protein and retinol binding protein-4 in normal pregnancy and preeclampsia. Clin Chim Acta 2009;407:58-61.
[37]Vaisbuch E, Romero R, Mazaki-Tovi S, et al. Retinol binding protein 4--a novel association with early-onset preeclampsia. J Perinat Med 2010; 38:129-39.
[38]Stepan H, Ebert T, Schrey S, et al. Preliminary report:Serum levels of retinol-binding protein 4 in preeclampsia. Metabolism 2009;58:275-7.
[39]Fasshauer M, Seeger J, Waldeyer T, et al. Serum levels of the adipokine adipocyte fatty acid-binding protein are increased in preeclampsia. Am J Hypertens 2008; 21:582-6.
[40]Cortelazzi D, Corbetta S, Ronzoni S, et al. Maternal and foetal resistin and adippnectin concentrations in normal and complicated pregnancies. Clin Endocrinol (Oxf) 2007;66:447-53.
[41]McPherron AC, Lee SJ. Suppression of body fat accumulation in myostatin-deficient mice. J Clin Invest 2002;109:595-601
[42]叶建伟.Myostatin对成肌细胞糖代谢的影响[D].中国协和医科大学；2006年
[43]Birdsall M, Ledger W, Groome N, Abdalla H, Muttukrishna S. Inhibin A and activin A in the first trimester of human pregnancy. J Clin Endocrinol Metab 1997; 82:1557-60.
[44]Muttukrishna S, George L, Fowler PA, Groome NP, Knight PG. Measurement of serum concentrations of inhibin-A (alpha-beta A dimer) during human pregnancy. Clin Endocrinol (Oxf) 1995;42:391-7.
[45]Muttukrishna S, North RA, Morri S, Schellenberg JC, Taylor RS, Asselin J, et al. Serum inhibin A and activin A are elevated prior to the onset of preeclampsia. Hum Reprod 2000; 15:1640-5
[46]Plevyak MP, Lambert-Messerliah GM, Farina A, Groome NP, Canick JA, Silver HM. Concentration of serum total activin A and inhibin A in preterm and term labor patients:a cross-sectional study. J Soc Gynecol Investig 2003;10:231-6.
[47]Muttukrishna S, Fowler PA, George L, Groome NP, Knight PG. Changes in peripheral serum levels of total activin A during the human menstrual cycle and pregnancy. J Clin Endocrinol Metab 1996; 81:3328-34.
[48]Sandra AF, Yvette PC, James FL, Arun J, W Allen H, Kirk PC. Altered global gene expression in first trimester placentas of women destined to develop preeclampsia. Placenta 2009;30:15-24
[1]Ji S, Losinski RL, Cornelius SG, et al. Myostatin expression in porcine tissues: tissue specificity and developmental and postnatal regulation [J]. Am J Physiol, 1998,275(4):1265-1273.
[2]Mendias, CL, Bakhurin KI, Faulkner JA. Tendons of myostatin-deficient mice are small, brittle, and hypocellular [J]. Proc Natl Acad Sci USA,2008,105(1): 388-393.
[3]Tortoriello DV, Sidis Y, Holtzman DA, et al. Human follistatin-related protein:a structural homologue of follistatin with nuclear localization [J]. Endocrinology, 2001,142(8):3426-3434.
[4]Hill JJ, Davies MV, Pearson AA, et al. The myostatin propeptide and the follistatin-related gene are inhibitory binding proteins of myostatin in normal serum [J]. J Biol Chem,2002,277(43):40735-40741.
[5]Hu S, Chen C, Sheng J, et al. Enhanced muscle growth by plasmid-mediated delivery of myostatin propeptide [J]. J Biomed Biotechnol,2010,2010:862591. Epub 2010 Mar 15.
[6]Zhao B, Wall RJ, Yang J. Transgenic expression of myostatin propetide prevents diet-induced obesity and insulin resistance [J]. Biochem Biophys Res Commun, 2006,337(1):248-255.
[7]Guo T, Jou W, Chanturiya T, et al. Myostatin inhibition in muscle, but not adipose tissue, decreases fat mass and improves insulin sensitivity [J]. Plos One,2009, 4(3):e4937.
[8]Wilkes JJ, Lloyd DJ, Gekakis N. Loss-of-function mutation in myostatin reduces tumor necrosis factor alpha production and protects liver against obesity-induced insulin resistance [J]. Diabetes,2009,58(5):1133-1143.
[9]Prakash A, Tuckerman E, Laird S, et al. A preliminary study comparing the endometrial expression of inhibin, activin and follistatin in women with a history of implantation failure after IVF treatment and a control group [J]. BJOG,2008, 115(4):532-537.
[10]Szabat M, Johnson JD, Piret JM. Reciprocal modulation of adult beta cell maturity by activin A and follistatin [J]. Diabetologia,2010,53 (8):1680-1689.
[11]Chen MJ, Chen HF, Chen SU, et al. The relationship between follistatin and chronic low-grade inflammation in women with poly cystic ovary syndrome [J]. Fertil Steril,2009,92(6):2041-2044.
[12]Haidet AM, Rizo L, Handy C, et al. Long-term enhancement of skeletal muscle and strength by single gene administration of myostatin inhibitors [J]. Proc Natl Acad Sci USA,2008,105(11):4318-4322.
[13]Medina J, Yamada S, Kojima I. Identification of differentially expressed genes during proliferative response of the liver induced by follistatin [J]. Endocr J,2009, 56(9):1067-1077.
[14]McCarthy C, Cotter FE, McElwaine S, et al. Altered gene expression patterns in intrauterine growth restriction:potential role of hypoxia [J]. Am J Obstet Gynecol, 2007,196(1):70.e1-6.
[15]Pryor-Koishi K, Nishizawa H, Kato T, et al. Overproduction of the follistatin-related gene protein in the placenta and maternal serum of women with pre-eclampsia [J]. BJOG,2007,114(9):1128-1137.
[16]Torres PB, Florio P, Ferreia MC, et al. Deranged expression of follistatin and follistatin-like protein in women with ovarian endometriosis [J]. Fertil Steril, 2007,88(1):200-205.
[17]Mukherjec A, Sidis Y, Mahan A, et al. FSTL3 deletion reveals roles for TGF-beta family ligands in glucose and fat homeostasis in adults [J]. Proc Natl Acad Sci USA,2007,104(4):1348-1353.
[18]Thadhani R, Powe CE, Tjoa ML, et al. First-trimester follistatin-like-3 levels in pregnancies complicated by subsequent gestational diabetes mellitus [J]. Diabetes Care,2010,33(3):664-669.
[19]Razanajaona D, Joguet S, Ay AS, et al. Silencing of FLRG, an antagonist of activin, inhibits human breast tumor cell growth [J]. Cancer Res,2007,67(15): 7223-7229.
[20]Mukherjec A, Sidis Y, Mahan A, et al. FSTL3 deletion reveals roles for TGF-beta family ligands in glucose and fat homeostasis in adults [J]. Proc Natl Acad Sci USA,2007,104(4):1348-1353.