PDF(1303 KB)
先天性心脏病胎儿心脏及胎盘组织中MAPK及Akt信号通路分子的变化
徐洁, 杨中州, 张姝, 吴少亘, 胡娅莉
中国当代儿科杂志 ›› 2010, Vol. 12 ›› Issue (05) : 327-332.
PDF(1303 KB)
PDF(1303 KB)
先天性心脏病胎儿心脏及胎盘组织中MAPK及Akt信号通路分子的变化
Changes of MAPK and Akt signaling pathways in hearts and placentas of aborted fetuses with congenital heart disease
目的：检测先天性心脏病(congenital heart disease，CHD)胎儿心脏及胎盘组织中MAPK及Akt信号通路分子表达变化，探讨其在CHD发病过程中的作用。方法：选取10例因患严重CHD/或同时伴其他缺陷而引产的胎儿，采用Western blot技术检测心脏左心室及胎盘组织中p38、p38α、p-p38、MEF2、ERK、p-ERK Akt、p-AktSer473、p-AktThr308蛋白表达量，采用半定量RT-PCR方法检测左心室p38α mRNA水平。7例孕龄相似、无CHD畸形儿为对照组。结果：①Western blot结果示：与对照组相比，CHD组中分别有4例心脏组织中p38及其亚型p38α、6例p-p38、2例MEF2、8例p-ERK、4例Akt及8例p-AktSer473和p-AktThr308蛋白水平降低，2例p-p38及1例p-AktThr308升高；CHD组中3例胎盘组织中p-p38上升，2例p-ERK下降。②CHD组MAPK及Akt信号通路蛋白表达量在胎儿心脏与胎盘组织中的变化不一致。③与对照组相比，4例p38α蛋白减少的心脏样本p38α异构体2 mRNA水平均降低，只有1例p38α异构体1、3、4 mRNA也减少。结论：CHD胎儿MAPK及Akt信号通路分子蛋白表达变化具有组织特异性，心脏组织中MAPK及Akt信号通路的异常可能与人类CHD的发生有关。［中国当代儿科杂志，2010，12（5）：327-332］
OBJECTIVE: To study the changes of MAPK and Akt signaling pathways in hearts and placentas of aborted fetuses with congenital heart disease (CHD), and investigate their roles in the pathogenesis of CHD. METHODS: Ten aborted fetuses with severe CHD (CHD group) and 7 gestational age-matched non-cardiac malformation aborted fetuses (control group) were enrolled. Western blot analysis was undertaken to assess the expression of p38, p38α, p-p38, MEF2, ERK, p-ERK, Akt, p-AktSer473 and p-AktThr308 in left ventricles and placentas of the fetuses, while semi-quantitative reverse transcription polymerase chain reaction analysis was used to detect the expression of p38α isoforms mRNA in hearts. RESULTS: Compared with the heart samples of the control group, the protein expression levels of p38 and its α isoform in 4 cases, p-p38 in 6 cases, MEF2 in 2 cases, p-ERK in 8 cases, Akt in 4 cases, p-AktSer473 and p-AktThr308 in 8 cases decreased, while the protein expression levels of p-p38 in 2 cases and p-AktThr308 in 1 case increased. P-p38 protein level in 3 cases and p-ERK protein level in 2 cases decreased in placentas compared with the control group. The changes of protein expression of MAPK and Akt signaling pathway in hearts were not consistent with those in placentas in the CHD group. The expression of p38α isoform2 mRNA showed descent tendency in 4 heart samples with CHD, while the expression of other three p38α isoforms mRNA was reduced in only 1 sample compared with the control group. CONCLUSIONS: Dysfunction of MAPK and Akt signaling pathways is tissue-specific in aborted fetuses with CHD. The perturbed two signaling pathways in hearts may contribute to the pathogenesis of human CHD.［Chin J Contemp Pediatr, 2010, 12 (5):327-332］
MAPK / Akt / 信号通路 / 先天性心脏病 / 胎儿
MAPK / Akt / Signaling pathway / Congenital heart disease / Fetus
［1］Botto LD, Correa A, Erickson JD. Racial and temporal variations in the revalence of heart defects［J］.Pediatrics, 2001, 107(3):E32.
［2］周建军,胡娅莉,刘启兰,陈启光,许碧云.江苏省以人群为基础的出生缺陷调查结果分析［J］.江苏医药, 2007, 33(12):1218-1220.
［3］杨江帆,许月珍,李萍,杨戎威.新生儿先天性心脏病患病率的调查和孕妇增补叶酸的预防效果［J］.中国当代儿科杂志,2000,2(5):320-325.
［4］中华医学会儿科学分会新生儿学组.中国住院新生儿流行病学调查［J］.中国当代儿科杂志, 2009, 11(1):15-20.
［5］Wang Y, Huang S, Sah VP, Ross J, Brown JH, Han J, et al. Cardiac muscle cell hypertrophy and apoptosis induced by distinct members of the p38 mitogen-activated protein kinase family［J］. J Biol Chem, 1998, 273(4):2161-2168.
［6］Davidson SM, Morange M. Hsp25 and the p38 MAPK pathway are involved in differentiation of cardiomyocytes［J］. Dev Biol, 2000, 218(2):146-160.
［7］Aoki Y, Niihori T, Narumi Y, Kure S, Matsubara Y. The RAS/MAPK syndromes: novel roles of the RAS pathway in human genetic disorders［J］. Hum Mutat, 2008, 29(8):992-1006.
［8］Yang ZZ, Tschopp O, Di-Poi N, Bruder E, Baudry A, Dummler B, et al. Dosage-depedent effects of Akt1/protein kinase Balpha(PKBalpha) and Akt3/PKBgamma on thymus, skin, and cardiovascular and nervous system development in mice［J］．Mol Cell Biol, 2005, 25(23):10407-10418.
［9］吴秀山.信号调控与心脏发育［M］.北京:化学工业出版社,2006:279-366;409-426.
［10］Adams RH, Porras A, Alonso G, Jones M, Vintersten K, Panelli S, et al. Essential role of p38alpha MAP kinase in placental but not embryonic cardiovascular development［J］. Mol Cell, 2000, 6(1): 109-116.
［11］Mudgett JS, Ding J, Guh-Siesel L, Chartrain NA, Yang L, Gopal S, et al. Essential role for p38alpha mitogen activated protein kinase in placental angiogenesis［J］. Proc Natl Acad Sci U S A, 2000, 97(19):10454-10459.
［12］Lin Q, Schwarz J, Bucana C, Olson EN. Control of mouse cardiac morphogenesis and myogenesis by transcription factor MEF2C［J］. Science, 1997, 276(5317):1404-1407.
［13］Naya FJ, Black BL, Wu H, Bassel-Duby R, Richardson JA, Hill JA, et al. Mitochondrial deficiency and cardiac sudden death in mice lacking the MEF2A transcription factor［J］. Nat Med, 2002, 8(11):1303-1309.
［14］Hernandez-Torres F, Martinez-Fernandez S, Zuluaga S, Nebreda A, Porras A, Aranega AE, et al. A role for p38alpha mitogen-activated protein kinase in embryonic cardiac differentiation［J］. FEBS Lett, 2008, 582(7):1025-1031.
［15］Yao Y, Li W, Wu J, Germann UA, Su MS, Kuida K, et al. Extracellular signal-regulated kinase 2 is necessary for mesoderm differentiation［J］. Proc Natl Acad Sci U S A, 2003,100(22):12759-12764.
［16］Nakamura T, Colbert M, Krenz M, Molkentin JD, Hahn HS, Dorn GW 2nd, et al. Mediating ERK 1/2 signaling rescues congenital heart defects in a mouse model of Noonan syndrome［J］. J Clin Invest, 2007, 117(8): 2123-2132.
［17］Cabane C, Coldefy AS, Yeow K, Derijard B. The p38 pathway regulates Akt both at protein and transcriptional activation levels during myogenesis［J］. Cell Signal, 2004, 16(12):1405-1415.
［18］Tan HY, Nicodemus KK, Chen Q, Li Z, Brooke JK, Honea R, et al. Genetic variation in AKT1 is linked to dopamine-associated prefrontal cortical structure and function in humans［J］. J Clin Invest, 2008, 118(6):2200-2208.
［19］束亚琴，常在，莫绪明，杨中州.Akt基因多态性与先天性心脏病发病关系的研究［J］.临床小儿外科杂志, 2009, 8(1):20-24.
［20］Senawong T, Phuchareon J, Ohara O, McCormick F, Rauen KA, Tetsu O. Germline mutations of MEK in cardio-facio-cutaneous syndrome are sensitive to MEK and RAF inhibition:implications for therapeutic options［J］. Hum Mol Genet, 2008, 17(3):419-430.
