BMPR2信号通路与先天性心脏病肺动脉高压发病机制的相关研究
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摘要
背景与目的:
先天性心脏病的发病率约为6-12‰。肺动脉高压(PAH)是左向右分流先天性心脏病最常见的并发症;而且严重的肺动脉高压如艾森曼格综合征将给临床治疗带来极大的困难。虽然对肺动脉高压的研究已有多年的历史,但其发病机制至今尚未完全清楚。近年来,骨形态生成蛋白Ⅱ型受体(BMPR2)在肺动脉高压的发病机制中的作用正日益受到重视。但以往对BMPR2信号通路的研究主要集中在特发性和家族性肺动脉高压上,目前并不清楚其在先天性心脏病肺动脉高压发病机制中的作用。为此,本课题拟以先天性心脏病室间隔缺损合并肺动脉高压的患者为代表,观察BMPR2及信号分子BMP4、Smad1在其肺组织中的变化;以及这些变化与肺组织细胞凋亡及内皮细胞功能障碍之间的关系,以进一步探讨先天性心脏病肺动脉高压的发生机制,并为临床的治疗提供新的靶点。
方法:
1.选取经手术治疗的62例室间隔缺损病例,根据术中测定的平均肺动脉压(mPAP),将患者分为4组。即无PAH组(mPAP<20mmHg、Ⅰ、n=12)、轻度PAH组(2150mmHg、Ⅳ、n=18)。
2.以实时相对定量RT-PCR及Western Blot法检测各组患者肺组织中BMP4、BMPR2的蛋白及mRNA表达情况;同时检测Smad1的磷酸化蛋白及mRNA的变化。
3.常规病理检测各组患者肺组织血管的变化,计算出管壁厚度占外径的百分比(WT%)、管壁面积占血管总面积的百分比(WA%) ,以反映肺组织血管管壁增厚程度。
4.以TUNEL法检测各组患者肺组织血管细胞凋亡的变化并计算凋亡指数(AI);以免疫组织化学法检测肺组织血管细胞中Bax、Bcl-2蛋白表达的变化;以免疫组织化学法及Western Blot法检测肺组织血管细胞中存活素(survivin)的表达变化。
5.以放射免疫法、硝酸还原酶法检测各组患者血浆中ET-1、NO的变化。
6.在上述实验结果的基础上,另将16例先天性心脏病室间隔缺损合并重度肺动脉高压患者随机分为对照组(n=8)及Bosentan治疗组(n=8),观察非选择性内皮素受体拮抗剂Bosentan对先天性心脏病重度肺动脉高压患者肺组织BMP4、BMPR2、Smad1mRNA表达的影响(实时相对定量RT-PCR)。
结果:
1.随着肺动脉压力水平的升高,患者肺组织中的BMP4mRNA、蛋白表达均有增高的趋势;而BMPR2mRNA、蛋白表达逐渐下降;Smad1mRNA及磷酸化蛋白表达也逐渐下降;统计学分析显示各组间均有显著性差异(P <0.05);提示在肺动脉高压患者肺组织中,BMPR2信号通路受到了抑制。BMP4、BMPR2、Smad1与mPAP之间均有显著相关性(P<0.05)。
2.随着肺动脉压力水平的升高,患者肺组织血管逐渐出现结构重构。重度PAH组肺组织血管壁增厚明显,出现血管壁平滑肌细胞肥大增生、动脉内膜细胞增生和胶原物质堆积性改变,管腔狭窄明显;WT%、WA%也逐渐增高。统计分析显示各组间均有显著性差异(P <0.05);BMP4、BMPR2、Smad1与WT%、WA%之间均有显著相关性(P<0.05)。
3.在中度、重度PAH组患者肺组织血管细胞中survivin、bcl-2表达明显增加;而bax表达明显减少,统计分析显示各组间均有显著性差异(P <0.05);BMP4、BMPR2、Smad1与survivin、bcl-2之间均有显著相关性(P<0.05)。
4.各组患者肺组织血管内均存在一定比例的凋亡细胞。中度、重度PAH组患者肺组织血管内凋亡细胞明显减少,凋亡指数(AI)明显下降。统计学分析显示各组间均有显著性差异(P <0.05);BMP4、BMPR2、Smad1与AI之间均有显著相关性(P<0.05)。
5.随着肺动脉压力水平的升高,患者血浆中ET-1的浓度也逐渐升高;但NO的浓度逐渐下降;统计分析显示各组间均有显著性差异(P <0.05);ET-1与mPAP之间有正相关性(P <0.05);而NO与mPAP负相关(P <0.05)。
6.Bosentan能抑制重度肺动脉高压患者肺组织BMP4mRNA的表达,但增加BMPR2mRNA、Smad1mRNA的表达,统计分析显示各组间均有显著性差异(P <0.05)。
结论:
1.在先天性心脏病肺动脉高压患者的肺组织中BMP4表达上调;但BMPR2、Smad1表达下调;BMPR2信号通路的信号传导最终受到了抑制。
2.受抑制的BMPR2信号通路可能通过促进survivin、bcl-2表达、抑制细胞凋亡而参与先天性心脏病肺动脉高压患者肺组织血管的结构重构。
3.在先天性心脏病肺动脉高压的发病过程中,BMPR2信号通路可能受到内皮素的影响;Bosentan不仅能拮抗异常的内皮素信号,而且还能改善BMPR2信号通路的信号传导。
Background and Objective
The incidence of congenital heart disease in live newborns was estimated from 6/1000 to 12/1000. Pulmonary arterial hypertension(PAH) is a major complication of congenital heart disease with left-to-right shunt. As determined by the level of pulmonary vascular resistance, the most severe form of Pulmonary arterial hypertension is Eisenmenger's syndrome, which is very dificult to treat. Pulmonary arterial hypertension has been widely investigated for decades. To date, the pathogenesis of Pulmonary arterial hypertension remains unclear, although many studies have focused on it. During the last few years, more and more evidences have demonstrated the role of bone morphogenetic protein receptor 2 in pathogenesis of pulmonary arterial hypertension. But previous research on BMPR2-associated signal pathway was mainly focused on idiopathic and familial pulmonary arterial hypertension, not on pulmonary arterial hypertension with congenital heart disease, which still needs to elucidate. Therefore, this study is designed to observe the changes of BMPR2 and its signal transmitting molecule BMP4, Smad1 in patients with pulmonary arterial hypertension complicated with ventricular septal defect and to investigate its relevance to apoptosis of pulmonary vascular cell and dysfunction of endothelial cell, aiming to explore the pathogenesis of pulmonary arterial hypertension and define a new target for the clinical treatment.
Methods
1. Sixty two patients underwent ventricular septal defect repaired were divided into 4 groups according to the mPAP measured during operation: group I with no PAH (mPAP<20mmHg, n=12), group II with slight PAH (2150mmHg, n=18).
2. Protein expression and mRNA of BMP4、BMPR2 of each patient were measured by real-time fluorescence quantitative RT-PCR and Western Blot . Phosphorylated protein and mRNA of Smad1 were also measured.
3. The pathomorphologic change was observed by HE stain.The changes of the vascular wall thickness/ vascular diameter (WT%)and vascular area/ total vascular area(WA%) were calculated.
4.Apoptosis was measured by TUNEL and apoptosis index(AI) was calculated. The protein expression of Bax and Bcl-2 were measured with immunohistochemical stain. Survivin was measured by immunohistochemical stain and Western Blot.
5. Before operation, 5mL venous blood was collected and plasma was separated. ET-1 and NO concentrations in plasma were measured with radioimmunoassay and nitric acid reductase.
6. Then, sixteen patients with severe PAH were randomly divided into control group (n=8) and bosentan group(n=8) treated with bosentan, a nonselective endothelin receptor antagonist. A real-time fluorescence quantitative RT-PCR assay was applied to evaluate the effects of bosentan on the mRNA expression of BMP4, BMPR2 and Smad1.
Results
1. With the increasing of mPAP, the mRNA and protein expression of BMP4 increased in lung tissue of patients, while the mRNA and protein expression of BMPR2, Smad1mRNA and phosphorylated protein decreased. There were statistical significant differences between each two groups (P<0.05). BMP4, BMPR2 and Smad1 were positively correlated with mPAP (P<0.05). The results suggested the BMPR2 signal pathway in lung tissue of PAH with CHD patients was restrained.
2. With the increasing of mPAP, pulmonary vascular remodelling appeared. The smooth muscle cells and endothelial cells in the tunica media of pulmonary vascular proliferated, the intima became thicken and collagen deposited in patients with CHD and PAH. Meanwhile, both WT% and WA% were gradually elevated. Statistic analysis showed that there was significant difference between each two groups(P <0.05). And there were significant correlations between BMP4、BMPR2、Smad1 and WT%, WA%(P <0.05).
3.In moderate and severe PAH groups, expression of survivin and bcl-2 increased while expression of bax decreased markedly. Statistic analysis showed that there were significant differences between each two groups(P <0.05). And there were significant correlations between BMP4, BMPR2, Smad1 and survivin, bcl-2(P <0.05).
4.Apoptosis was observed in the lung of all the patients. Apoptosis apparently decreased in the lung tissue of group III and group IV. The difference of AI among 4 groups was significant ( P<0.05). There were significant correlations between BMP4、BMPR2、Smad1 and AI(P <0.05).
5. With the aggravation of PAH, ET-1 plasma concentration increased while NO plasma concentration decreased. Statistic analysis showed that there were significant differences among each two groups(P <0.05). There were significant correlation between ET-1 and mPAP(P <0.05) and significant negative correlation between NO and mPAP(P <0.05).
6. Bosentan could inhibit the expression of BMP4mRHA in the lung tissue of patients with severe pulmonary arterial hypertension and promote the expression of BMPR2mRNA and Smad1mRNA. The difference was significant between the control group and treatment group(.P<0.05).
Conclusion
1.The BMPR2 signal pathway is restrained because of the decreased expression of BMPR2 and Smad1, in spite of the increased expression of BMP4 in pulmonary arterial hypertension with congenital heart disease.
2.The restrained BMPR2 signal pathway might repress cell apoptosis by promoting the expression of survivin and bcl-2 and suggest a significant participation in pulmonary vascular remodeling in pulmonary arterial hypertension with congenital heart disease.
3. BMPR2 signal pathway might be impacted by ET-1, Bosentan can improve the dysfunctional ET-1 and BMP signal pathways in pulmonary arterial hypertension with congenital heart disease.
先天性心脏病的发病率约为6-12‰。肺动脉高压(PAH)是左向右分流先天性心脏病最常见的并发症;而且严重的肺动脉高压如艾森曼格综合征将给临床治疗带来极大的困难。虽然对肺动脉高压的研究已有多年的历史,但其发病机制至今尚未完全清楚。近年来,骨形态生成蛋白Ⅱ型受体(BMPR2)在肺动脉高压的发病机制中的作用正日益受到重视。但以往对BMPR2信号通路的研究主要集中在特发性和家族性肺动脉高压上,目前并不清楚其在先天性心脏病肺动脉高压发病机制中的作用。为此,本课题拟以先天性心脏病室间隔缺损合并肺动脉高压的患者为代表,观察BMPR2及信号分子BMP4、Smad1在其肺组织中的变化;以及这些变化与肺组织细胞凋亡及内皮细胞功能障碍之间的关系,以进一步探讨先天性心脏病肺动脉高压的发生机制,并为临床的治疗提供新的靶点。
方法:
1.选取经手术治疗的62例室间隔缺损病例,根据术中测定的平均肺动脉压(mPAP),将患者分为4组。即无PAH组(mPAP<20mmHg、Ⅰ、n=12)、轻度PAH组(21
2.以实时相对定量RT-PCR及Western Blot法检测各组患者肺组织中BMP4、BMPR2的蛋白及mRNA表达情况;同时检测Smad1的磷酸化蛋白及mRNA的变化。
3.常规病理检测各组患者肺组织血管的变化,计算出管壁厚度占外径的百分比(WT%)、管壁面积占血管总面积的百分比(WA%) ,以反映肺组织血管管壁增厚程度。
4.以TUNEL法检测各组患者肺组织血管细胞凋亡的变化并计算凋亡指数(AI);以免疫组织化学法检测肺组织血管细胞中Bax、Bcl-2蛋白表达的变化;以免疫组织化学法及Western Blot法检测肺组织血管细胞中存活素(survivin)的表达变化。
5.以放射免疫法、硝酸还原酶法检测各组患者血浆中ET-1、NO的变化。
6.在上述实验结果的基础上,另将16例先天性心脏病室间隔缺损合并重度肺动脉高压患者随机分为对照组(n=8)及Bosentan治疗组(n=8),观察非选择性内皮素受体拮抗剂Bosentan对先天性心脏病重度肺动脉高压患者肺组织BMP4、BMPR2、Smad1mRNA表达的影响(实时相对定量RT-PCR)。
结果:
1.随着肺动脉压力水平的升高,患者肺组织中的BMP4mRNA、蛋白表达均有增高的趋势;而BMPR2mRNA、蛋白表达逐渐下降;Smad1mRNA及磷酸化蛋白表达也逐渐下降;统计学分析显示各组间均有显著性差异(P <0.05);提示在肺动脉高压患者肺组织中,BMPR2信号通路受到了抑制。BMP4、BMPR2、Smad1与mPAP之间均有显著相关性(P<0.05)。
2.随着肺动脉压力水平的升高,患者肺组织血管逐渐出现结构重构。重度PAH组肺组织血管壁增厚明显,出现血管壁平滑肌细胞肥大增生、动脉内膜细胞增生和胶原物质堆积性改变,管腔狭窄明显;WT%、WA%也逐渐增高。统计分析显示各组间均有显著性差异(P <0.05);BMP4、BMPR2、Smad1与WT%、WA%之间均有显著相关性(P<0.05)。
3.在中度、重度PAH组患者肺组织血管细胞中survivin、bcl-2表达明显增加;而bax表达明显减少,统计分析显示各组间均有显著性差异(P <0.05);BMP4、BMPR2、Smad1与survivin、bcl-2之间均有显著相关性(P<0.05)。
4.各组患者肺组织血管内均存在一定比例的凋亡细胞。中度、重度PAH组患者肺组织血管内凋亡细胞明显减少,凋亡指数(AI)明显下降。统计学分析显示各组间均有显著性差异(P <0.05);BMP4、BMPR2、Smad1与AI之间均有显著相关性(P<0.05)。
5.随着肺动脉压力水平的升高,患者血浆中ET-1的浓度也逐渐升高;但NO的浓度逐渐下降;统计分析显示各组间均有显著性差异(P <0.05);ET-1与mPAP之间有正相关性(P <0.05);而NO与mPAP负相关(P <0.05)。
6.Bosentan能抑制重度肺动脉高压患者肺组织BMP4mRNA的表达,但增加BMPR2mRNA、Smad1mRNA的表达,统计分析显示各组间均有显著性差异(P <0.05)。
结论:
1.在先天性心脏病肺动脉高压患者的肺组织中BMP4表达上调;但BMPR2、Smad1表达下调;BMPR2信号通路的信号传导最终受到了抑制。
2.受抑制的BMPR2信号通路可能通过促进survivin、bcl-2表达、抑制细胞凋亡而参与先天性心脏病肺动脉高压患者肺组织血管的结构重构。
3.在先天性心脏病肺动脉高压的发病过程中,BMPR2信号通路可能受到内皮素的影响;Bosentan不仅能拮抗异常的内皮素信号,而且还能改善BMPR2信号通路的信号传导。
Background and Objective
The incidence of congenital heart disease in live newborns was estimated from 6/1000 to 12/1000. Pulmonary arterial hypertension(PAH) is a major complication of congenital heart disease with left-to-right shunt. As determined by the level of pulmonary vascular resistance, the most severe form of Pulmonary arterial hypertension is Eisenmenger's syndrome, which is very dificult to treat. Pulmonary arterial hypertension has been widely investigated for decades. To date, the pathogenesis of Pulmonary arterial hypertension remains unclear, although many studies have focused on it. During the last few years, more and more evidences have demonstrated the role of bone morphogenetic protein receptor 2 in pathogenesis of pulmonary arterial hypertension. But previous research on BMPR2-associated signal pathway was mainly focused on idiopathic and familial pulmonary arterial hypertension, not on pulmonary arterial hypertension with congenital heart disease, which still needs to elucidate. Therefore, this study is designed to observe the changes of BMPR2 and its signal transmitting molecule BMP4, Smad1 in patients with pulmonary arterial hypertension complicated with ventricular septal defect and to investigate its relevance to apoptosis of pulmonary vascular cell and dysfunction of endothelial cell, aiming to explore the pathogenesis of pulmonary arterial hypertension and define a new target for the clinical treatment.
Methods
1. Sixty two patients underwent ventricular septal defect repaired were divided into 4 groups according to the mPAP measured during operation: group I with no PAH (mPAP<20mmHg, n=12), group II with slight PAH (21
2. Protein expression and mRNA of BMP4、BMPR2 of each patient were measured by real-time fluorescence quantitative RT-PCR and Western Blot . Phosphorylated protein and mRNA of Smad1 were also measured.
3. The pathomorphologic change was observed by HE stain.The changes of the vascular wall thickness/ vascular diameter (WT%)and vascular area/ total vascular area(WA%) were calculated.
4.Apoptosis was measured by TUNEL and apoptosis index(AI) was calculated. The protein expression of Bax and Bcl-2 were measured with immunohistochemical stain. Survivin was measured by immunohistochemical stain and Western Blot.
5. Before operation, 5mL venous blood was collected and plasma was separated. ET-1 and NO concentrations in plasma were measured with radioimmunoassay and nitric acid reductase.
6. Then, sixteen patients with severe PAH were randomly divided into control group (n=8) and bosentan group(n=8) treated with bosentan, a nonselective endothelin receptor antagonist. A real-time fluorescence quantitative RT-PCR assay was applied to evaluate the effects of bosentan on the mRNA expression of BMP4, BMPR2 and Smad1.
Results
1. With the increasing of mPAP, the mRNA and protein expression of BMP4 increased in lung tissue of patients, while the mRNA and protein expression of BMPR2, Smad1mRNA and phosphorylated protein decreased. There were statistical significant differences between each two groups (P<0.05). BMP4, BMPR2 and Smad1 were positively correlated with mPAP (P<0.05). The results suggested the BMPR2 signal pathway in lung tissue of PAH with CHD patients was restrained.
2. With the increasing of mPAP, pulmonary vascular remodelling appeared. The smooth muscle cells and endothelial cells in the tunica media of pulmonary vascular proliferated, the intima became thicken and collagen deposited in patients with CHD and PAH. Meanwhile, both WT% and WA% were gradually elevated. Statistic analysis showed that there was significant difference between each two groups(P <0.05). And there were significant correlations between BMP4、BMPR2、Smad1 and WT%, WA%(P <0.05).
3.In moderate and severe PAH groups, expression of survivin and bcl-2 increased while expression of bax decreased markedly. Statistic analysis showed that there were significant differences between each two groups(P <0.05). And there were significant correlations between BMP4, BMPR2, Smad1 and survivin, bcl-2(P <0.05).
4.Apoptosis was observed in the lung of all the patients. Apoptosis apparently decreased in the lung tissue of group III and group IV. The difference of AI among 4 groups was significant ( P<0.05). There were significant correlations between BMP4、BMPR2、Smad1 and AI(P <0.05).
5. With the aggravation of PAH, ET-1 plasma concentration increased while NO plasma concentration decreased. Statistic analysis showed that there were significant differences among each two groups(P <0.05). There were significant correlation between ET-1 and mPAP(P <0.05) and significant negative correlation between NO and mPAP(P <0.05).
6. Bosentan could inhibit the expression of BMP4mRHA in the lung tissue of patients with severe pulmonary arterial hypertension and promote the expression of BMPR2mRNA and Smad1mRNA. The difference was significant between the control group and treatment group(.P<0.05).
Conclusion
1.The BMPR2 signal pathway is restrained because of the decreased expression of BMPR2 and Smad1, in spite of the increased expression of BMP4 in pulmonary arterial hypertension with congenital heart disease.
2.The restrained BMPR2 signal pathway might repress cell apoptosis by promoting the expression of survivin and bcl-2 and suggest a significant participation in pulmonary vascular remodeling in pulmonary arterial hypertension with congenital heart disease.
3. BMPR2 signal pathway might be impacted by ET-1, Bosentan can improve the dysfunctional ET-1 and BMP signal pathways in pulmonary arterial hypertension with congenital heart disease.
引文
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