Akt/PTEN在低氧肺血管重建中的作用和机制研究
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摘要
肺动脉平滑肌细胞(PASMCs)从中膜大量迁移至内膜并异常增殖是低氧肺动脉高压肺血管重建的基本病理变化。在此病理过程中,多种细胞因子、生长因子通过细胞内信号传递途径将细胞外增殖信号传至核内,在核内调节基因表达,启动细胞增殖反应。
目前探讨低氧肺动脉高压(hypoxia pulmonary hypertension,HPH)中血管重建的细胞内信号传导通路的研究主要集中在STATs途径、MLCK途径和PKC途径。丝氨酸/苏氨酸蛋白激酶Akt (serine/threonine kinase,Akt)参与的经磷脂酰肌醇3激酶(phosphoinositide 3 kinase,PI3K)激活的细胞内信号通路与细胞分化、生长、凋亡和迁移等多种生物学活动密切相关。与细胞张力蛋白同源在10号染色体有缺失的磷酸酶(phosohatase and tensin homolog deleted on chromosome 10,PTEN)迄今为止发现的第一个具有脂质磷酸酶活性的抑癌基因。其功能是对脂质第二信使PI-3,4,5-P3进行3位脱磷酸,从而降低细胞内PIP3水平,下调Akt通路。本课题建立体外PASMCs培养模型,观察低氧培养时PASMCs Akt/PTEN信号通路中主要信号分子表达和活性的变化;并通过Ad-PTEN转染上调PTEN的表达,研究PTEN活性变化对低氧条件下PASMCs增殖和迁移的影响,以阐明Akt/PTEN信号通路调控低氧诱导PASMCs异常增殖及迁移的作用及机制,明确这一信号通路中参与肺血管重建的关键环节,从而为HPH的防治提供理论依据。
研究内容:
1 .原代培养PASMCs并鉴定后, RT-PCR检测常氧及低氧条件下PTEN/Akt1/Akt2/Akt3基因mRNA表达变化;免疫细胞化学和Western blot法检测上述基因蛋白定位和表达变化。
2.Ad-PTEN的扩增、鉴定、转染效率、MOI、滴度测定。
3.RT-PCR和Western blot检测Ad-PTEN转染后细胞PTEN基因mRNA表达及其蛋白活性变化。MTT、3H-TdR掺入实验和流式细胞仪检测常氧及低氧条件下Ad-PTEN转染前后细胞增殖变化。
4.Ad-PTEN转染后常氧及低氧条件下PASMCs平面迁移距离的变化。
5.RT-PCR和Western blot检测常氧及低氧条件下转染前后细胞Akt1/Akt2/Akt3 mRNA表达变化。
结果:
1.原代培养的大鼠PASMCs经α-SM-actin免疫细胞化学染色得到证实,并冻存第四代细胞。组织块法和酶法培养的PASMC的生长曲线和蛋白质含量上有一定程度上的差异,但差异并不显著(p>0.05),二者均于7～8 d达高峰,而后由于接触抑制而下降。组织块法培养PASMC的胞内[Ca2+]含量为(195.32±14.62) nmol/L,而酶消化法为(150.18±11.87) nmol/l,差异有显著性意义(P<0.05)。
2.常氧及低氧条件下PASMCs中,RT-PCR、Western blot法在常氧条件下PASMCs中检测到PTEN/Akt1,2,3基因的表达;在低氧刺激下,PTEN的mRNA和蛋白水平均逐渐升高;低氧刺激下2h PASMCs中Akt1,2,3表达升高,6 h达高峰,12 h下降,24 h恢复到常氧水平,其mRNA和蛋白表达变化一致;免疫细胞化学结果示PTEN蛋白在PASMCs胞浆和胞核中均表达;Akt1,2,3仅在胞浆中表达。
3.扩增并冻存了Ad-PTEN(CVL液)约2ml。滴度大约1.03×109 pfu/ml。经鉴定所得到的重组腺病毒确实携带着外源性目的基因PTEN片段。Ad-PTEN对PASMCs有较高的感染效率,最佳MOI为60。Ad-PTEN转染PASMCs后,PTEN在PASMCs中明显过表达。在低氧刺激下,Ad-PTEN的转染仍然能够保证PTEN在PASMCs中过表达。
4.MTT检测发现低氧刺激下,PASMCs增殖明显增强并且随着低氧处理时间的延长而进一步升高,Ad-PTEN转染组PASMCs增殖明显低于未转染组。3H-TdR掺入检测发现未转染组低氧时PASMCs的3H-TdR掺入量比常氧时升高,而Ad-PTEN转染后PASMCs的3H-TdR掺入量明显低于未转染组。流式细胞仪结果显示低氧使未转染组PASMCs的G0/G1比例降低,而S+G2/M比例升高,Ad-PTEN转染使PASMCs中PTEN基因表达增强以后,低氧仅使转染组PASMCs的G0/G1比例稍有降低,但降低不显著。
5.常氧培养的PASMCs随着培养时间的延长,迁移的距离逐渐增加,其中与36h比较,48h和72h的迁移距离增加有显著性意义(p<0.05)。在低氧刺激下,PASMCs迁移的距离显著行增加。Ad-PTEN转染组PASMCs迁移的距离较常氧组以及低氧处理组显著性减少。
6.PASMCs Akt1,2,3 mRNA表达量在低氧2 h开始升高,6h达高峰,12 h开始降低,24 h下降至常氧水平。而Ad-PTEN转染后PASMCs Akt1 mRNA表达量升高幅度较小,各时相点间无显著差异。
结论:
1.正常大鼠PASMCs检测到PTEN/Akt1,2,3基因表达。低氧可刺激大鼠PASMCs S PTEN/Akt1,2,3基因表达增强。
2.扩增的Ad-PTEN能够转染PASMCs并在细胞中高效的过表达PTEN。
3.低氧可能通过诱导PTEN/Akt的表达和活化促进PASMCs增殖,其中Akt的表达和活化可能起主要作用。而Ad-PETN转染能够抑制低氧刺激导致的PASMCs增殖。
4.低氧可能通过诱导PTEN/Akt的表达和活化促进PASMCs迁移,其中Akt的表达和活化可能起主要作用。而Ad-PETN转染能够抑制低氧刺激导致的PASMCs迁移。
5. Ad-PTEN转染PASMCs致细胞内过表达PTEN能够显著性抑制Akt1,2,3基因的转录,可能是Ad-PTEN转染抑制低氧刺激导致的PASMCs增殖和迁移的分子基础。
A great deal of pulmonary artery smooth muscle cells (PASMCs) migrating from tunica media to endomemebrane and abnomal proliferating is an improtant contributor to the vascular remodeling that occurs in chronic hypoxic pulmonary hypertension (HPH). Different growth factors, cytokine and proinflammatory mediators convey extracelluar signal to the nucleus by interacting with receptors on the cell surface, then regulate expression of target genes and contribute to cell differentiation, growth and proliferation.
Now the main studies about signal transmitting passway of vascular remodeling in HPH focused on STATs passway, MLCK passway and PKC passway. Serine/threonine kinase (Akt) participates in the signal transduction actived by phosphoinositide 3 kinase (PI3K), which is closely correlated to cell differentiation,cell growth,apoptosis,migration and other biological actions. Phosohatase and tensin homolog deleted on chromosome 10(PTEN) is the first discovered anticoncogene with lipid-phosphatase activity so far. PTEN can carry out 3-location dephosphorylation, that can lower the level of PIP3 in cell and down regulate Akt signal condutive passway. When hypoxia actived intracellular signal transdutive passway and inducted a series of pathological actions of (PASMCs phenotype switching, proliferation and migration ), what role did the PTEN/Akt play in hypoxia lung vascular remodeling? Along the nature course of disease, whether the expression of PTEN/Akt descended even depleted?
Methods
1. After PASMCs were primarily cultured, expression of PTEN/Akt1,2,3 mRNA was detected by RT-PCR under normoxic or hypoxia conditions (3% O2); expressions of SOCS3 proteins were performed by immunocytochemistry and Western blot under normoxic or hypoxia conditions.
2. Amplification, appraisement, transfective effciency,MOI and titre measuration of Ad-PTEN.
3. The PASMCs transfected with Ad-PTEN and the control cells were cultured under normoxic and hypoxia conditions respectively. The expression of PTEN mRNA and protein activity were performed by RT-PCR and Western blot. The changes of cell proliferation were observed by MTT,flow cytometric DNA analysis and 3H-TdR incorporation.
4. After PASMCs transfected with Ad-PTEN, level of migratory distance was detected under normoxia or hypoxia conditions.
5. Expression of Akt1,2,3 mRNA in PASMCs before and after transfection were detected by RT-PCR under normoxic and hypoxia conditions.
Results
1. Rat PASMCs primarily cultured were confirmed by immunocytochemistry usingα-SM-actin antibody. The fourth generation was freezed and reserved. There existed a certain extent of degree diversity in growth curve and protein content of PASMCs between cultured by tissue clump or enzymic method, but it was not remarkable(p>0.05). Both reached its peak after 7~8d, and then declined due to contact inhibition. The content of intracellular Ca2+ of PASMC cultured by tissue clump method was (195.32±14.62) nmol/L, and (150.18±11.87) nmol/l by the enzymic method. The difference between both was obvious (P<0.05).
2. Expression of PTEN/Akt1,2,3 mRNA and proteins in PASMCs was detected by RT-PCR and western blot under normoxic and hypoxia conditions. When PASMCs were cultured under hypoxia conditions, the level of expression of PTEN mRNA and protein gradually heightened. The experession of Akt1,2,3 mRNA was detected highter at 2 h of hypoxia and reached its maximal at 6 h or 12 h, declined to previous normoxic level at 24 h. The change of protein expression induced by hypoxia was similar to that of mRNA. Immunocytochemistry was used to confirm Akt1,2,3 protein only related to cytoplasmic distribution of rat PASMCs,but PTEN protein dealt with to be both in cytoplasmic and mucelus distribution both.
3. About 2 ml Ad-PTEN was freezed after amplification. The titer was about 1.03×109 pfu/ml. It was identificated that the exogenous objective gene PTEN fragment existed in recombinative adenovirus. Ad-PTEN has high efficiency of infection for PASMCs, and the best MOI was 60. The hyperexpression of PTEN gene was found in PASMCs after Ad-PTEN transfection, And that was the same under hypoxia condition.
4. In MTT study, proliferation of PASMCs was enhanced and was hypoxia time lengthen related. The proliferation of PASMCs in transfected by Ad-PTEN decresed obviouly. 3H-TdR incorporation increased obviously in hypoxia in contrast to normoxia condition. And 3H-TdR incorporation n transfected by Ad-PTEN began to decrease obviously. In contrast to the same hour in normal PASMCs exposed to hypoxia, cells transfected with Ad-PTEN at G0/G1 increased, cells in S+G2/M decreased significantly.
5. In normoxia culture, the migratory distance of PASMCs gradually increased along with cultivate time prolongation. The migratory distance in 48h and 72h increased obviously in contrast to 36h(p<0.05). The hypoxia could stimulate PASMCs migration. The migratory distance in infected by Ad-PTEN cells decreased obviously no matter whether it was under normoxic or hypoxia condition.
6. The expression of Akt1,2,3 mRNA increased after exposure of cells to hypoxia and reached its maximum at 6 h, then declined at 12 h, and decreased to level of normoxia at 24h. The magnitude of expression enhancement of Akt1,2,3 mRNA in PTEN gene-transfected cells were significantly lower than that in normal PASMCs whether under normoxic or hypoxia condition.
Conclusions
1. Akt1,2,3 and PTEN mRNA and proteins are detected in rat PASMCs exposed to normoxia. Hypoxia can stimulate the expression intensity of Akt1,2,3 and PTEN.
2. Ad-PTEN amplificated can transfect PASMCs and caused hyperexpress PTEN in cells.
3. Maybe hypoxia promotes proliferation of PASMCs through inducting the expression and activation of PTEN/Akt. And the expression of activation of Akt may plays a more important role.
4. Hypoxia may promotes migration of PASMCs through inducting the expression and activation of PTEN/Akt. And the expression of activation of Akt plays a more important role.
5. Hyperexpressive PTEN in Ad-PTEN transfected PASMCs can obviously inhibit the transcription of Akt1,2,3. that maybe the molecular basis of Ad-PTEN inhibit the proliferation and imgration of PASMCs under hypoxia condition.
目前探讨低氧肺动脉高压(hypoxia pulmonary hypertension,HPH)中血管重建的细胞内信号传导通路的研究主要集中在STATs途径、MLCK途径和PKC途径。丝氨酸/苏氨酸蛋白激酶Akt (serine/threonine kinase,Akt)参与的经磷脂酰肌醇3激酶(phosphoinositide 3 kinase,PI3K)激活的细胞内信号通路与细胞分化、生长、凋亡和迁移等多种生物学活动密切相关。与细胞张力蛋白同源在10号染色体有缺失的磷酸酶(phosohatase and tensin homolog deleted on chromosome 10,PTEN)迄今为止发现的第一个具有脂质磷酸酶活性的抑癌基因。其功能是对脂质第二信使PI-3,4,5-P3进行3位脱磷酸,从而降低细胞内PIP3水平,下调Akt通路。本课题建立体外PASMCs培养模型,观察低氧培养时PASMCs Akt/PTEN信号通路中主要信号分子表达和活性的变化;并通过Ad-PTEN转染上调PTEN的表达,研究PTEN活性变化对低氧条件下PASMCs增殖和迁移的影响,以阐明Akt/PTEN信号通路调控低氧诱导PASMCs异常增殖及迁移的作用及机制,明确这一信号通路中参与肺血管重建的关键环节,从而为HPH的防治提供理论依据。
研究内容:
1 .原代培养PASMCs并鉴定后, RT-PCR检测常氧及低氧条件下PTEN/Akt1/Akt2/Akt3基因mRNA表达变化;免疫细胞化学和Western blot法检测上述基因蛋白定位和表达变化。
2.Ad-PTEN的扩增、鉴定、转染效率、MOI、滴度测定。
3.RT-PCR和Western blot检测Ad-PTEN转染后细胞PTEN基因mRNA表达及其蛋白活性变化。MTT、3H-TdR掺入实验和流式细胞仪检测常氧及低氧条件下Ad-PTEN转染前后细胞增殖变化。
4.Ad-PTEN转染后常氧及低氧条件下PASMCs平面迁移距离的变化。
5.RT-PCR和Western blot检测常氧及低氧条件下转染前后细胞Akt1/Akt2/Akt3 mRNA表达变化。
结果:
1.原代培养的大鼠PASMCs经α-SM-actin免疫细胞化学染色得到证实,并冻存第四代细胞。组织块法和酶法培养的PASMC的生长曲线和蛋白质含量上有一定程度上的差异,但差异并不显著(p>0.05),二者均于7～8 d达高峰,而后由于接触抑制而下降。组织块法培养PASMC的胞内[Ca2+]含量为(195.32±14.62) nmol/L,而酶消化法为(150.18±11.87) nmol/l,差异有显著性意义(P<0.05)。
2.常氧及低氧条件下PASMCs中,RT-PCR、Western blot法在常氧条件下PASMCs中检测到PTEN/Akt1,2,3基因的表达;在低氧刺激下,PTEN的mRNA和蛋白水平均逐渐升高;低氧刺激下2h PASMCs中Akt1,2,3表达升高,6 h达高峰,12 h下降,24 h恢复到常氧水平,其mRNA和蛋白表达变化一致;免疫细胞化学结果示PTEN蛋白在PASMCs胞浆和胞核中均表达;Akt1,2,3仅在胞浆中表达。
3.扩增并冻存了Ad-PTEN(CVL液)约2ml。滴度大约1.03×109 pfu/ml。经鉴定所得到的重组腺病毒确实携带着外源性目的基因PTEN片段。Ad-PTEN对PASMCs有较高的感染效率,最佳MOI为60。Ad-PTEN转染PASMCs后,PTEN在PASMCs中明显过表达。在低氧刺激下,Ad-PTEN的转染仍然能够保证PTEN在PASMCs中过表达。
4.MTT检测发现低氧刺激下,PASMCs增殖明显增强并且随着低氧处理时间的延长而进一步升高,Ad-PTEN转染组PASMCs增殖明显低于未转染组。3H-TdR掺入检测发现未转染组低氧时PASMCs的3H-TdR掺入量比常氧时升高,而Ad-PTEN转染后PASMCs的3H-TdR掺入量明显低于未转染组。流式细胞仪结果显示低氧使未转染组PASMCs的G0/G1比例降低,而S+G2/M比例升高,Ad-PTEN转染使PASMCs中PTEN基因表达增强以后,低氧仅使转染组PASMCs的G0/G1比例稍有降低,但降低不显著。
5.常氧培养的PASMCs随着培养时间的延长,迁移的距离逐渐增加,其中与36h比较,48h和72h的迁移距离增加有显著性意义(p<0.05)。在低氧刺激下,PASMCs迁移的距离显著行增加。Ad-PTEN转染组PASMCs迁移的距离较常氧组以及低氧处理组显著性减少。
6.PASMCs Akt1,2,3 mRNA表达量在低氧2 h开始升高,6h达高峰,12 h开始降低,24 h下降至常氧水平。而Ad-PTEN转染后PASMCs Akt1 mRNA表达量升高幅度较小,各时相点间无显著差异。
结论:
1.正常大鼠PASMCs检测到PTEN/Akt1,2,3基因表达。低氧可刺激大鼠PASMCs S PTEN/Akt1,2,3基因表达增强。
2.扩增的Ad-PTEN能够转染PASMCs并在细胞中高效的过表达PTEN。
3.低氧可能通过诱导PTEN/Akt的表达和活化促进PASMCs增殖,其中Akt的表达和活化可能起主要作用。而Ad-PETN转染能够抑制低氧刺激导致的PASMCs增殖。
4.低氧可能通过诱导PTEN/Akt的表达和活化促进PASMCs迁移,其中Akt的表达和活化可能起主要作用。而Ad-PETN转染能够抑制低氧刺激导致的PASMCs迁移。
5. Ad-PTEN转染PASMCs致细胞内过表达PTEN能够显著性抑制Akt1,2,3基因的转录,可能是Ad-PTEN转染抑制低氧刺激导致的PASMCs增殖和迁移的分子基础。
A great deal of pulmonary artery smooth muscle cells (PASMCs) migrating from tunica media to endomemebrane and abnomal proliferating is an improtant contributor to the vascular remodeling that occurs in chronic hypoxic pulmonary hypertension (HPH). Different growth factors, cytokine and proinflammatory mediators convey extracelluar signal to the nucleus by interacting with receptors on the cell surface, then regulate expression of target genes and contribute to cell differentiation, growth and proliferation.
Now the main studies about signal transmitting passway of vascular remodeling in HPH focused on STATs passway, MLCK passway and PKC passway. Serine/threonine kinase (Akt) participates in the signal transduction actived by phosphoinositide 3 kinase (PI3K), which is closely correlated to cell differentiation,cell growth,apoptosis,migration and other biological actions. Phosohatase and tensin homolog deleted on chromosome 10(PTEN) is the first discovered anticoncogene with lipid-phosphatase activity so far. PTEN can carry out 3-location dephosphorylation, that can lower the level of PIP3 in cell and down regulate Akt signal condutive passway. When hypoxia actived intracellular signal transdutive passway and inducted a series of pathological actions of (PASMCs phenotype switching, proliferation and migration ), what role did the PTEN/Akt play in hypoxia lung vascular remodeling? Along the nature course of disease, whether the expression of PTEN/Akt descended even depleted?
Methods
1. After PASMCs were primarily cultured, expression of PTEN/Akt1,2,3 mRNA was detected by RT-PCR under normoxic or hypoxia conditions (3% O2); expressions of SOCS3 proteins were performed by immunocytochemistry and Western blot under normoxic or hypoxia conditions.
2. Amplification, appraisement, transfective effciency,MOI and titre measuration of Ad-PTEN.
3. The PASMCs transfected with Ad-PTEN and the control cells were cultured under normoxic and hypoxia conditions respectively. The expression of PTEN mRNA and protein activity were performed by RT-PCR and Western blot. The changes of cell proliferation were observed by MTT,flow cytometric DNA analysis and 3H-TdR incorporation.
4. After PASMCs transfected with Ad-PTEN, level of migratory distance was detected under normoxia or hypoxia conditions.
5. Expression of Akt1,2,3 mRNA in PASMCs before and after transfection were detected by RT-PCR under normoxic and hypoxia conditions.
Results
1. Rat PASMCs primarily cultured were confirmed by immunocytochemistry usingα-SM-actin antibody. The fourth generation was freezed and reserved. There existed a certain extent of degree diversity in growth curve and protein content of PASMCs between cultured by tissue clump or enzymic method, but it was not remarkable(p>0.05). Both reached its peak after 7~8d, and then declined due to contact inhibition. The content of intracellular Ca2+ of PASMC cultured by tissue clump method was (195.32±14.62) nmol/L, and (150.18±11.87) nmol/l by the enzymic method. The difference between both was obvious (P<0.05).
2. Expression of PTEN/Akt1,2,3 mRNA and proteins in PASMCs was detected by RT-PCR and western blot under normoxic and hypoxia conditions. When PASMCs were cultured under hypoxia conditions, the level of expression of PTEN mRNA and protein gradually heightened. The experession of Akt1,2,3 mRNA was detected highter at 2 h of hypoxia and reached its maximal at 6 h or 12 h, declined to previous normoxic level at 24 h. The change of protein expression induced by hypoxia was similar to that of mRNA. Immunocytochemistry was used to confirm Akt1,2,3 protein only related to cytoplasmic distribution of rat PASMCs,but PTEN protein dealt with to be both in cytoplasmic and mucelus distribution both.
3. About 2 ml Ad-PTEN was freezed after amplification. The titer was about 1.03×109 pfu/ml. It was identificated that the exogenous objective gene PTEN fragment existed in recombinative adenovirus. Ad-PTEN has high efficiency of infection for PASMCs, and the best MOI was 60. The hyperexpression of PTEN gene was found in PASMCs after Ad-PTEN transfection, And that was the same under hypoxia condition.
4. In MTT study, proliferation of PASMCs was enhanced and was hypoxia time lengthen related. The proliferation of PASMCs in transfected by Ad-PTEN decresed obviouly. 3H-TdR incorporation increased obviously in hypoxia in contrast to normoxia condition. And 3H-TdR incorporation n transfected by Ad-PTEN began to decrease obviously. In contrast to the same hour in normal PASMCs exposed to hypoxia, cells transfected with Ad-PTEN at G0/G1 increased, cells in S+G2/M decreased significantly.
5. In normoxia culture, the migratory distance of PASMCs gradually increased along with cultivate time prolongation. The migratory distance in 48h and 72h increased obviously in contrast to 36h(p<0.05). The hypoxia could stimulate PASMCs migration. The migratory distance in infected by Ad-PTEN cells decreased obviously no matter whether it was under normoxic or hypoxia condition.
6. The expression of Akt1,2,3 mRNA increased after exposure of cells to hypoxia and reached its maximum at 6 h, then declined at 12 h, and decreased to level of normoxia at 24h. The magnitude of expression enhancement of Akt1,2,3 mRNA in PTEN gene-transfected cells were significantly lower than that in normal PASMCs whether under normoxic or hypoxia condition.
Conclusions
1. Akt1,2,3 and PTEN mRNA and proteins are detected in rat PASMCs exposed to normoxia. Hypoxia can stimulate the expression intensity of Akt1,2,3 and PTEN.
2. Ad-PTEN amplificated can transfect PASMCs and caused hyperexpress PTEN in cells.
3. Maybe hypoxia promotes proliferation of PASMCs through inducting the expression and activation of PTEN/Akt. And the expression of activation of Akt may plays a more important role.
4. Hypoxia may promotes migration of PASMCs through inducting the expression and activation of PTEN/Akt. And the expression of activation of Akt plays a more important role.
5. Hyperexpressive PTEN in Ad-PTEN transfected PASMCs can obviously inhibit the transcription of Akt1,2,3. that maybe the molecular basis of Ad-PTEN inhibit the proliferation and imgration of PASMCs under hypoxia condition.
引文
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