孕鼠暴露于炎症、免疫刺激剂诱发子代高血压机制研究：发病相关候选基因的筛选
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摘要
原发性高血压(essential hypertension,EH)是最常见的心血管疾病,其并发症是造成人类死亡的主要原因之一。探索EH的发病机制、寻找EH的防治方法有极其重要的意义。炎症在心血管疾病发病中重要作用的认识是近年来该领域最重要的进展之一。更为有趣的是,越来越多的临床流行病学调查结果提示高血压在某些方面也与炎症密切相关。我室近年研究发现,孕鼠暴露于炎症刺激剂LPS或免疫刺激剂zymosan后,可导致仔鼠出生后血压升高、体重增加;近年发育生物学提出“成人慢性病的胎源性学说”,即成人一些慢性疾病如冠心病、Ⅱ型糖尿病、高血压等的病因源于胚胎及婴幼儿时期发育的可塑性,也就是在妊娠期间,始儿受到来自外界环境的刺激会对其发育产生影响,并可能对其成年后发生一些慢性疾病起重要作用,这一理论正与我们的研究发现相吻合。但究竟这种炎症免疫刺激因素是通过那一些因子和途径来引起胎儿发育上的改变导致仔鼠成年后发生血压升高和体重增加,目前还未见相关报道。鉴于此,本研究拟在我室原有的研究工作的基础上,探讨炎症免疫刺激因素是如何影响胎儿的发育,研究炎症免疫刺激孕鼠对胚胎全基因表达的影响,旨在探索仔鼠高血压发病相关的候选基因,为进一步深入了解其分子机制和寻找有效干预措施提供新线索和理论依据。
方法
1.SD孕鼠,在妊娠8、10、12天,分别腹腔注射0.79 mg/kg LPS、8 mg/kg zymosan为炎症免疫刺激模型,对照组腹腔注射生理盐水。
2.在最后一次注射后2小时鼠尾取血,及取最后一次注射后2h、12h、24h及48h的羊水混合,用放免法检测血清及羊水的TNF-α及IL-6水平。
3.实时荧光定量PCR分析胎盘、羊膜、羊水中细胞、胚胎及腹腔巨噬细胞中的TNF-α及IL-6 mRNA水平。
4.Affymetrix的大鼠全基因组芯片研究炎症免疫刺激模型与正常对照之间胚胎的基因表达谱的变化。
5.基因芯片数据采用Gene Onology分析生物学功能,采用GenMAPP2.1软件分析信号通路。GO分析我们重点放在分子功能分析上。
6.选择了20个基因采用实时荧光定量PCR验证基因芯片结果,并研究这些基因在胚胎不同时相点的表达变化情况。
结果与结论
1.应用孕鼠腹腔注射LPS、zymosan,血清TNF-α、IL-6水平较对照组明显升高(P＜0.01),说明在LPS和Zym组,母鼠均发生了炎症免疫反应;TNF-αmRNA水平在巨噬细胞中表达最多,3h时是其它组织的上千倍;IL-6 mRNA在巨噬细胞中表达最多,2h时是其它细胞的几十万倍。说明炎性因子TNF-α、IL-6主要来源于巨噬细胞一类炎性细胞。
2.在胚胎中TNF-αmRNA的量较低,而IL-6 mRNA的量较其他几种组织中高,并且炎症刺激组在24h及48h两个时相点要明显高于对照组数十倍,提示IL-6与大鼠妊娠期注射炎症免疫刺激剂引起仔代大鼠血压升高有关;在羊膜、羊水及胎盘中LPS组明显高于对照组,而Zym组则仅在胎盘中变化明显,提示两种炎症免疫刺激剂作用路径不尽相同,LPS可以通过影响羊膜,羊水及胎盘的细胞因子变化而影响胚胎发育;zymosan则主要通过胎盘影响胚胎的发育。
3.用大鼠全基因芯片从28 000个基因中发现孕鼠注射炎症、免疫刺激剂后胚胎的差异表达基因:LPS组上调(Ratio≥2)的有183个、下调(Ratio≤0.5)的有270个;Zym组上调(Ratio≥2)的有144个、下调(Ratio≤0.5)的有417个。LPS组及Zym组中同向变化的基因,上调的有50个,其中功能已知的基因有10个(Tnnt2,Arg1,Fgf8,Dusp9,Plekhf1,Soat1,Fubp1,Orc11,Hmga1,Nr2f6);下调的有173个,其中功能已知的基因有85个。
4.Gene Ontology功能检索,差异表达基因数量较多的功能分类集中在结合分子、催化活性、转运体、信号转导及转录调节等几个方面,涉及生长因子、细胞信号转导的蛋白和核转录因子,直接参与代谢的酶,肌钙蛋白等。其中表达下调的基因比表达上调的多,这种胚胎期的基因表达下调可能会影响仔鼠以后的发育。
5.GenMAPP信号通路的可视化分析,发现在DNA合成、RNA加工、细胞G1期到S期调控及翻译因子方面,有差异表达的基因基本是都是上调,而且在LPS组及Zym组中呈高度的一致性;在心肌钙调节、平滑肌收缩舒张通路及炎症反应通路中则下调的基因较多。
6.选择了20个差异表达基因,采用实时荧光定量PCR技术对芯片结果进行验证。在12h时与基因芯片数据一致的有13个、不一致的有4个,还有RGD1307150、Bcl11a及Tgfb2三个基因的Zym组与芯片结果一致。
7.各基因的mRNA含量变化中:Fgf8、Orcl1在2h及12h时实验组较对照组出现了上调,24h到48h逐渐降到对照组同一水平;Bcl11a、Dusp9表现与上述相反;Nfib的mRNA水平在实验组中各时相点均有不同程度的下调;Egfr、Gap43及Penk1的mRNA水平在2h时三个组相差不明显,在12h到48h实验组出现了不同程度的下调;Agtr2在12h时实验组明显低于对照组Tgfb2在Zym组各时相点都有下调,而LPS组则没有。结合各基因功能分析:Fgf8、Orc11、Bcl11a的表达变化可能与炎症免疫刺激后胚胎的急性期调节有关;Nfia、Nfib及Gap43的表达下调可能与炎症免疫刺激对胚胎脑发育的影响有关;Agtr2的表达下调可能会对仔鼠肾脏的发育产生一定的影响;Dusp9、Egfr、Ripx及Tgfb2等的表达变化可能与炎症免疫刺激对胚胎细胞增殖分化的影响有关。这些影响是否与炎症免疫刺激引起仔鼠血压升高有关还有待进一步的实验研究。
Essential hypertension(EH) is one of the most common cardiovascular disease.And the complication caused by EH is one the main cause of human fatility.So it is important that investigation of the mechanism of EH for prevention and cure EH.Recently significant progress has been made in understanding the effect of inflammation on cardiovascular disease.More and more data from clinic practice and research tells us that hypertension is related with inflammation in certain ways.In the past research of our own team,we found that prenatal exposure to LPS or zymosan result in increases in blood pressure and body weight in rats offspring.This also is accordance with the modern developmental biology proposes "Fetal-Oringin Theory for Adult Chronic Diseases".The theory suggest that developmental plasticity of embryo and infant cause some adult chronicle diseases such as coronary heart disease,type2 diabetes,hypertension.That is to say that exterior stimulation during preganency may play a key role in chronicle adult disease.Together with our data support the possibility of the existence of this relationship.However,we want to know more fundamental answer:what factors and channels affect the growth of fetius after those exterior stimulation.Based on our research team,this essay intends to study how immuno-inflammatory stimulation affect the development of embryo.Through Affymetrix's GeneChip Rat Genome 230 Arrays,the gene expression profiles between immuno-inflammatory group and control group is studied.
Methods
1.Sprague-Dawley(SD) rats,dams in each group received i.p injections of 0.79 mg/kg LPS,8 mg/kg zymosan or sterile saline respectively on their gestational days 8,10,and 12.
2.The serums were collected in tail nick at 2 h after the last injection,and the amniotic fluid was mixed at 2 h,12 h,24 h,48 h after the last injection.TNF-αand IL-6 levels of serum and amniotic fluid were measured by RIA method.
3.TNF-αand IL-6 mRNA levels were quantitated in amnion,placenta,amniotic fluid, Embryo and macrophage by real-time fluorescent quantitative-PCR.
4.Gene expression profiles of each group was observed by Affymetrix's GeneChip Rat Genome 230 Arrays.
5.The data of GeneChip were analyzed with Gene Ontology and GenMAPP for the biology function and the signal pathway.
6.Twenty differentially expressed genes were selected to confirm the GeneChip data by real-time fluorescent quantitative-PCR.And these genes were studied in each group embryo by real-time fluorescent quantitative-PCR,
Results and Conclusion
1.The serum level of TNF-αand IL-6 in LPS group and zymosan group was higher than that in control group(P＜0.01).It showed that there was immuno-imflammatory response after LPS or zymosan injection in rats.The mRNA levels of TNF-αand IL-6 was very higher in macrophage than in other organization.
2.In embryo,the mRNA level of IL-6 was more than other organization,but the mRNA level of TNF-αwas lower than other organization.However,the IL-6 mRNA levelof LPS group and zymosan group was higher several dozens times than control group on 24h and 48h.It suggested that IL-6 was important in the model that prenatalexposure to immuno-inflammatory stimulant results in increases of blood pressure and body weight in rats.
3.Among the total 28000 genes on the GeneChip,in LPS group,183 genes were found to be higher expression(Ratio≥2 ) and 270 genes were lower expression(Ratio≤0.5 );in Zymosan group,144 genes were found to be higher expression(Ratio≥2 ) and 417 genes were lower expression(Ratio≤0.5 ).However,both in two group,50 genes were found to be higher expression(Ratio≥2 ) and 173 genes were lower expression(Ratio≤0.5 ).
4.The data of genechip was analyzed with Gene Ontology for biology function.It is showed that the differentially expressed genes were sorted into binding,catalytic activity, transporter activity,signal transducer activity or transcription regulator on GO Molecular Function.
5.The data of genechip was analyzed by GenMAPP software for signal pathway.It showed that in DNA replication,mRNA processing,translation factors,the differentially expressed genes were up-regulation in the LPS group and Zymosan group.And in calcium regulation in cardiac cell,smooth muscle contraction pathways,inflammatory response pathways,the down-regulation expressed genes are more than up-regulaion.
6.We detected the mRNA level of 20 genes by real-time PCR,and found that 13 genes was consistent with the genechip data,but 4 genes was inconsistent.And the zymosan group of RGD1307150,Bcl11a,Tgfb2 were consistent with the genechip data.
7.In the embryos of rats with immunolgy inflammation,real-time PCR show that the FgfS,Orc11 increased at 2 h,12 h point and down to normal level at 24 h and 48 h compared with control group.However,the profile of Bcl11a,Dusp9 mRNA appeared reverse.The level of Nfib mRNA decrease in every time point.The Egfr,Gap43,Penk1 remain normal at 2 h and just decreased at 12 h to 48 h.The Agtr2 was lower than control at 12 h.The Tgfb2 in zymosan group decreased at all point,but no change in the LPS group. With the genes function,we presumed that Fgf8,Orcll,Bcl11a might be correlated with acute regulation of immuno-inflammatory stimulus.Nfia,Nfib,Gap43 might be correlated with efforts of immuno-inflammatory stimulus on embryo's brain development,and Agtr2 might be on kidney development.Dusp9,Egfr,Ripx,Tgfb2 might be correlated with efforts of immuno-inflammatory stimulus on the proliferation and differentiation of embryo cell. However,the relationship between these efforts and prenatal exposure to immunoinflammatory stimulus results in increases of blood pressure was for further research.
方法
1.SD孕鼠,在妊娠8、10、12天,分别腹腔注射0.79 mg/kg LPS、8 mg/kg zymosan为炎症免疫刺激模型,对照组腹腔注射生理盐水。
2.在最后一次注射后2小时鼠尾取血,及取最后一次注射后2h、12h、24h及48h的羊水混合,用放免法检测血清及羊水的TNF-α及IL-6水平。
3.实时荧光定量PCR分析胎盘、羊膜、羊水中细胞、胚胎及腹腔巨噬细胞中的TNF-α及IL-6 mRNA水平。
4.Affymetrix的大鼠全基因组芯片研究炎症免疫刺激模型与正常对照之间胚胎的基因表达谱的变化。
5.基因芯片数据采用Gene Onology分析生物学功能,采用GenMAPP2.1软件分析信号通路。GO分析我们重点放在分子功能分析上。
6.选择了20个基因采用实时荧光定量PCR验证基因芯片结果,并研究这些基因在胚胎不同时相点的表达变化情况。
结果与结论
1.应用孕鼠腹腔注射LPS、zymosan,血清TNF-α、IL-6水平较对照组明显升高(P＜0.01),说明在LPS和Zym组,母鼠均发生了炎症免疫反应;TNF-αmRNA水平在巨噬细胞中表达最多,3h时是其它组织的上千倍;IL-6 mRNA在巨噬细胞中表达最多,2h时是其它细胞的几十万倍。说明炎性因子TNF-α、IL-6主要来源于巨噬细胞一类炎性细胞。
2.在胚胎中TNF-αmRNA的量较低,而IL-6 mRNA的量较其他几种组织中高,并且炎症刺激组在24h及48h两个时相点要明显高于对照组数十倍,提示IL-6与大鼠妊娠期注射炎症免疫刺激剂引起仔代大鼠血压升高有关;在羊膜、羊水及胎盘中LPS组明显高于对照组,而Zym组则仅在胎盘中变化明显,提示两种炎症免疫刺激剂作用路径不尽相同,LPS可以通过影响羊膜,羊水及胎盘的细胞因子变化而影响胚胎发育;zymosan则主要通过胎盘影响胚胎的发育。
3.用大鼠全基因芯片从28 000个基因中发现孕鼠注射炎症、免疫刺激剂后胚胎的差异表达基因:LPS组上调(Ratio≥2)的有183个、下调(Ratio≤0.5)的有270个;Zym组上调(Ratio≥2)的有144个、下调(Ratio≤0.5)的有417个。LPS组及Zym组中同向变化的基因,上调的有50个,其中功能已知的基因有10个(Tnnt2,Arg1,Fgf8,Dusp9,Plekhf1,Soat1,Fubp1,Orc11,Hmga1,Nr2f6);下调的有173个,其中功能已知的基因有85个。
4.Gene Ontology功能检索,差异表达基因数量较多的功能分类集中在结合分子、催化活性、转运体、信号转导及转录调节等几个方面,涉及生长因子、细胞信号转导的蛋白和核转录因子,直接参与代谢的酶,肌钙蛋白等。其中表达下调的基因比表达上调的多,这种胚胎期的基因表达下调可能会影响仔鼠以后的发育。
5.GenMAPP信号通路的可视化分析,发现在DNA合成、RNA加工、细胞G1期到S期调控及翻译因子方面,有差异表达的基因基本是都是上调,而且在LPS组及Zym组中呈高度的一致性;在心肌钙调节、平滑肌收缩舒张通路及炎症反应通路中则下调的基因较多。
6.选择了20个差异表达基因,采用实时荧光定量PCR技术对芯片结果进行验证。在12h时与基因芯片数据一致的有13个、不一致的有4个,还有RGD1307150、Bcl11a及Tgfb2三个基因的Zym组与芯片结果一致。
7.各基因的mRNA含量变化中:Fgf8、Orcl1在2h及12h时实验组较对照组出现了上调,24h到48h逐渐降到对照组同一水平;Bcl11a、Dusp9表现与上述相反;Nfib的mRNA水平在实验组中各时相点均有不同程度的下调;Egfr、Gap43及Penk1的mRNA水平在2h时三个组相差不明显,在12h到48h实验组出现了不同程度的下调;Agtr2在12h时实验组明显低于对照组Tgfb2在Zym组各时相点都有下调,而LPS组则没有。结合各基因功能分析:Fgf8、Orc11、Bcl11a的表达变化可能与炎症免疫刺激后胚胎的急性期调节有关;Nfia、Nfib及Gap43的表达下调可能与炎症免疫刺激对胚胎脑发育的影响有关;Agtr2的表达下调可能会对仔鼠肾脏的发育产生一定的影响;Dusp9、Egfr、Ripx及Tgfb2等的表达变化可能与炎症免疫刺激对胚胎细胞增殖分化的影响有关。这些影响是否与炎症免疫刺激引起仔鼠血压升高有关还有待进一步的实验研究。
Essential hypertension(EH) is one of the most common cardiovascular disease.And the complication caused by EH is one the main cause of human fatility.So it is important that investigation of the mechanism of EH for prevention and cure EH.Recently significant progress has been made in understanding the effect of inflammation on cardiovascular disease.More and more data from clinic practice and research tells us that hypertension is related with inflammation in certain ways.In the past research of our own team,we found that prenatal exposure to LPS or zymosan result in increases in blood pressure and body weight in rats offspring.This also is accordance with the modern developmental biology proposes "Fetal-Oringin Theory for Adult Chronic Diseases".The theory suggest that developmental plasticity of embryo and infant cause some adult chronicle diseases such as coronary heart disease,type2 diabetes,hypertension.That is to say that exterior stimulation during preganency may play a key role in chronicle adult disease.Together with our data support the possibility of the existence of this relationship.However,we want to know more fundamental answer:what factors and channels affect the growth of fetius after those exterior stimulation.Based on our research team,this essay intends to study how immuno-inflammatory stimulation affect the development of embryo.Through Affymetrix's GeneChip Rat Genome 230 Arrays,the gene expression profiles between immuno-inflammatory group and control group is studied.
Methods
1.Sprague-Dawley(SD) rats,dams in each group received i.p injections of 0.79 mg/kg LPS,8 mg/kg zymosan or sterile saline respectively on their gestational days 8,10,and 12.
2.The serums were collected in tail nick at 2 h after the last injection,and the amniotic fluid was mixed at 2 h,12 h,24 h,48 h after the last injection.TNF-αand IL-6 levels of serum and amniotic fluid were measured by RIA method.
3.TNF-αand IL-6 mRNA levels were quantitated in amnion,placenta,amniotic fluid, Embryo and macrophage by real-time fluorescent quantitative-PCR.
4.Gene expression profiles of each group was observed by Affymetrix's GeneChip Rat Genome 230 Arrays.
5.The data of GeneChip were analyzed with Gene Ontology and GenMAPP for the biology function and the signal pathway.
6.Twenty differentially expressed genes were selected to confirm the GeneChip data by real-time fluorescent quantitative-PCR.And these genes were studied in each group embryo by real-time fluorescent quantitative-PCR,
Results and Conclusion
1.The serum level of TNF-αand IL-6 in LPS group and zymosan group was higher than that in control group(P＜0.01).It showed that there was immuno-imflammatory response after LPS or zymosan injection in rats.The mRNA levels of TNF-αand IL-6 was very higher in macrophage than in other organization.
2.In embryo,the mRNA level of IL-6 was more than other organization,but the mRNA level of TNF-αwas lower than other organization.However,the IL-6 mRNA levelof LPS group and zymosan group was higher several dozens times than control group on 24h and 48h.It suggested that IL-6 was important in the model that prenatalexposure to immuno-inflammatory stimulant results in increases of blood pressure and body weight in rats.
3.Among the total 28000 genes on the GeneChip,in LPS group,183 genes were found to be higher expression(Ratio≥2 ) and 270 genes were lower expression(Ratio≤0.5 );in Zymosan group,144 genes were found to be higher expression(Ratio≥2 ) and 417 genes were lower expression(Ratio≤0.5 ).However,both in two group,50 genes were found to be higher expression(Ratio≥2 ) and 173 genes were lower expression(Ratio≤0.5 ).
4.The data of genechip was analyzed with Gene Ontology for biology function.It is showed that the differentially expressed genes were sorted into binding,catalytic activity, transporter activity,signal transducer activity or transcription regulator on GO Molecular Function.
5.The data of genechip was analyzed by GenMAPP software for signal pathway.It showed that in DNA replication,mRNA processing,translation factors,the differentially expressed genes were up-regulation in the LPS group and Zymosan group.And in calcium regulation in cardiac cell,smooth muscle contraction pathways,inflammatory response pathways,the down-regulation expressed genes are more than up-regulaion.
6.We detected the mRNA level of 20 genes by real-time PCR,and found that 13 genes was consistent with the genechip data,but 4 genes was inconsistent.And the zymosan group of RGD1307150,Bcl11a,Tgfb2 were consistent with the genechip data.
7.In the embryos of rats with immunolgy inflammation,real-time PCR show that the FgfS,Orc11 increased at 2 h,12 h point and down to normal level at 24 h and 48 h compared with control group.However,the profile of Bcl11a,Dusp9 mRNA appeared reverse.The level of Nfib mRNA decrease in every time point.The Egfr,Gap43,Penk1 remain normal at 2 h and just decreased at 12 h to 48 h.The Agtr2 was lower than control at 12 h.The Tgfb2 in zymosan group decreased at all point,but no change in the LPS group. With the genes function,we presumed that Fgf8,Orcll,Bcl11a might be correlated with acute regulation of immuno-inflammatory stimulus.Nfia,Nfib,Gap43 might be correlated with efforts of immuno-inflammatory stimulus on embryo's brain development,and Agtr2 might be on kidney development.Dusp9,Egfr,Ripx,Tgfb2 might be correlated with efforts of immuno-inflammatory stimulus on the proliferation and differentiation of embryo cell. However,the relationship between these efforts and prenatal exposure to immunoinflammatory stimulus results in increases of blood pressure was for further research.
引文
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