瑞舒伐他汀对野百合碱所致大鼠肺动脉高压的干预及机制研究
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摘要
目的
建立野百合碱诱导的大鼠肺动脉高压模型,探讨骨形成蛋白受体-II信号转导在肺动脉高压发病机制中的作用,观察瑞舒伐他汀防治该模型肺动脉高压的作用及可能机制。
方法
采用一次性皮下注射1%野百合碱(MCT)50mg/Kg建立SD大鼠肺动脉高压模型,正常组仅予皮下注射生理盐水,在大鼠形成肺动脉高压之前和之后分别给予瑞舒伐他汀灌胃进行预防和治疗实验。预防实验:32只雄性SD大鼠随机均分为:正常4周组(N4)、模型4周组(M4)、瑞舒伐他汀低剂量预防组(2mg/kg/d,R2p)、瑞舒伐他汀高剂量预防组(10mg/kg/d,R10p)。R2p、R10p组于野百合碱注射当日起每日给与瑞舒伐他汀灌胃,N4、M4组仅予生理盐水灌胃,干预4周;治疗实验:48只雄性SD大鼠随机分为4组:正常8周组(N8)8只、模型8周组(M8)16只、瑞舒伐他汀低剂量治疗组(2mg/kg/d,R2t)12只、瑞舒伐他汀高剂量治疗组(10mg/kg/d,R10t)12只;R2t、R10t组于野百合碱注射第4周末起每日给与瑞舒伐他汀灌胃,N8、M8组仅予生理盐水灌胃,干预4周。观察各组大鼠的一般情况及生存率,各组干预结束后测量平均右心室压力(mRVP)、平均肺动脉压力(mPAP)和右心室肥厚指数[RV/ (LV+S)];HE染色观察肺小动脉管壁厚度与血管外径之比(WT%)和管壁面积占血管总面积的百分比(WA%);免疫组化染色方法检测BMPR-Ⅱ蛋白在肺小动脉中的表达;Western Blot法检测BMPR-Ⅱ、Smad4蛋白在肺组织中的表达含量。
结果
1存活情况:预防实验各组大鼠实验结束时存活率为100%,治疗实验在8周末实验结束时N8、M8、R2t和R10t各组存活率分别为100%、25%、58.3%、75%,相对于M8组R2t和R10t组的存活率明显升高(P<0.05)。
2血流动力学测定、肺小动脉形态学观察及右心室肥厚指数计算:与N4组相比,M4组mRVP、mPAP、RV/( LV+S)显著升高(P<0.01),肺小动脉管壁明显增厚,管腔狭窄,WT%、WA%显著升高(P<0.01)。与M4组相比,R2p组、R10p组中mRVP、mPAP、RV/( LV+S)、WT%、WA%均明显下降(P<0.05),以R10p组下降更明显,与R2p组比较差异有统计学意义(P<0.05),但均未恢复到N4组水平(P<0.01)。治疗组结果与预防组类似。
3肺小动脉BMPR-Ⅱ蛋白表达:N4组BMPR-Ⅱ蛋白大量表达,M4组表达显著下降(P<0.01);R2p组、R10p组表达较M4组不同程度升高(P<0.05),剂量间有统计学差异(P<0.05),但均未恢复到N4组水平(P<0.01)。治疗组结果与预防组类似。
4肺组织BMPR-Ⅱ蛋白、Smad4蛋白的表达量:N4组BMPR-Ⅱ蛋白、Smad4蛋白表达量较多,M4组表达量显著减少(P<0.01);R2p组、R10p组表达量较M4组有不同程度增加(P<0.05),剂量间有统计学差异(P<0.05),但均未恢复到N4组水平(P<0.01)。治疗组结果与预防组类似。
结论
野百合碱可诱导大鼠肺小动脉平滑肌增生和肥厚、肺小血管重构和右心室肥厚,形成肺动脉高压;瑞苏伐他汀可延缓野百合碱诱导的肺动脉高压的形成和缓解已经形成的肺动脉高压,减轻右室肥厚,这一机制可能是通过上升肺小动脉BMPR-Ⅱ、Smad4蛋白的表达实现的。
Objectives:
To explore the effect of morphogentic protein receptor-II signal transduction in the pathogenesis of monocrotaline-induced pulmonary hypertension in rat, and the preventive and therapeutic effects of rosuvastatin on model of PAH.
Methods:
Rats received a single subcutaneous injection of monocrotaline(MCT,50 mg/kg), to induces pulmonary arterial hypertension. Normal control rats were just injected with saline .Rats received prevention and treatmen with rosuvastatin before and after development of pulmonary arterial hypertension. In the prevention protocol:32 male Sprague-Dawley rats were randomly divided into four groups: normal control group (4 weeks) (N4),model control group(4 weeks)(M4), low-dose rosuvastatin prevention group(2mg/kg/d,R2p),high-dose rosuvastatin prevention group(10mg/kg/d,R10p). From the day MCT injection on, rats in R2p and R10p groups were prevented with rosuvastatin by daily gavage for 4 weeks. rats in N4 and M4 groups just received vehicle by gavage. In the treatment protocol:48 male Sprague-Dawley rats were randomly divided into four groups: normal control group(N8,n=8),pulmonary arterial hypertension group(M8,n=16),low-dose rosuvastatin treatment group(2mg/kg/d, R2t,n=12),high-dose rosuvastatin treatment group(10mg/kg/d,R10t,n=12);Four weeks after MCT injection, rats in R2t and R10t groups were treated with rosuvastatin by daily gavage for 4 weeks . rats in N8 and M8 groups just received vehicle by gavage. state and death were observed. When the prevention and treatment ended,polyethylene catheters were inserted into the RV through the jugular vein for hemodynamic measurements. Mean right ventricular pressure(mRVP) and mean pulmonary artery pressure(mPAP) were measured with a polygraph system.RV hypertrophy index[RV/ (LV+S)] was also measured. Arteries of 50 to 150μm were evaluated for the median wall thickness and wall area by HE staining as follows: percent wall thickness(WT%)= [(medial thickness×2/external diameter)]×100 and percent wall area (WT%)= (wall area / total area)×100. The level of BMPR-II protein expression in pulmonary artery were assessed by immunohistochemistry. Western blot was used to assess Changes of BMPR-II and Smad4 protein expression in lung tissue.
Results:
1 state and survival analysis:At 4 th weekend,all rats in the prevention protocol survived.At 8 th weekend,survival rates of N8、M8、R2t and R10t group were 100%、25%、58.3%、75% in the treatment protocol. Compared with M8 group, the survival rate of R2t and R10t group were also markedly increased(P<0.05)
2 Hemodynamics,pulmonary vascular morphology and right ventricular hypertrophy assessment: compared with N4 group,M4 group rats exhibited higher mRVP , mPAP and RV/ (LV+S) (P<0.01), arteriole endomembrane ,medial thickness,WT% and WA% were also markedly increased(P<0.01). Compared with M4 group ,R2p and R10p groups exhibited lower mRVP、mPAP、RV/ (LV+S)、WT% and WA% (P<0.05),and have statistical difference between doses(P<0.05),but have statistical difference compared with N4 group(P<0.01). The results in the treatment protocol were similar to those in the prevention protocol.
3 BMPR-II protein expression in small pulmonary artery: compared to N4 group,the expression of BMPR-II protein markedly decreased in M4 group(P<0.01);it increased in R2p and R10p groups compared to M4 group(P<0.05); and have statistical difference between doses(P<0.05),but have statistical difference compared with N4 group(P<0.01). The results in the treatment protocol were similar to those in the prevention protocol.
4 BMPR-II and Smad4 protein expressions in lung tissue: compared to N4 group,the expression of BMPR-II protein and Smad4 protein markedly decreased in M4 group(P<0.01);it increased in R2p and R10p groups compared to M4 group(P<0.05); and have statistical difference between doses(P<0.05),but have statistical difference compared with N4 group(P<0.01). The results in the treatment protocol were similar to those in the prevention protocol.
Conclusion:
MCT induced proliferation of pulmonary VSMC、pulmonary artery remodeling and RV hypertrophy in rats. Rosuvastatin lowered pulmonary artery hypertension, decreased right ventricular hypertrophy. The mechanisms of preventive and therapeutic effects of rosuvastatin on monocrotaline-induced pulmonary arterial hypertension may be contributed to up-regulate the expression of BMPR-II and Smad4 protein in lung tissue.
建立野百合碱诱导的大鼠肺动脉高压模型,探讨骨形成蛋白受体-II信号转导在肺动脉高压发病机制中的作用,观察瑞舒伐他汀防治该模型肺动脉高压的作用及可能机制。
方法
采用一次性皮下注射1%野百合碱(MCT)50mg/Kg建立SD大鼠肺动脉高压模型,正常组仅予皮下注射生理盐水,在大鼠形成肺动脉高压之前和之后分别给予瑞舒伐他汀灌胃进行预防和治疗实验。预防实验:32只雄性SD大鼠随机均分为:正常4周组(N4)、模型4周组(M4)、瑞舒伐他汀低剂量预防组(2mg/kg/d,R2p)、瑞舒伐他汀高剂量预防组(10mg/kg/d,R10p)。R2p、R10p组于野百合碱注射当日起每日给与瑞舒伐他汀灌胃,N4、M4组仅予生理盐水灌胃,干预4周;治疗实验:48只雄性SD大鼠随机分为4组:正常8周组(N8)8只、模型8周组(M8)16只、瑞舒伐他汀低剂量治疗组(2mg/kg/d,R2t)12只、瑞舒伐他汀高剂量治疗组(10mg/kg/d,R10t)12只;R2t、R10t组于野百合碱注射第4周末起每日给与瑞舒伐他汀灌胃,N8、M8组仅予生理盐水灌胃,干预4周。观察各组大鼠的一般情况及生存率,各组干预结束后测量平均右心室压力(mRVP)、平均肺动脉压力(mPAP)和右心室肥厚指数[RV/ (LV+S)];HE染色观察肺小动脉管壁厚度与血管外径之比(WT%)和管壁面积占血管总面积的百分比(WA%);免疫组化染色方法检测BMPR-Ⅱ蛋白在肺小动脉中的表达;Western Blot法检测BMPR-Ⅱ、Smad4蛋白在肺组织中的表达含量。
结果
1存活情况:预防实验各组大鼠实验结束时存活率为100%,治疗实验在8周末实验结束时N8、M8、R2t和R10t各组存活率分别为100%、25%、58.3%、75%,相对于M8组R2t和R10t组的存活率明显升高(P<0.05)。
2血流动力学测定、肺小动脉形态学观察及右心室肥厚指数计算:与N4组相比,M4组mRVP、mPAP、RV/( LV+S)显著升高(P<0.01),肺小动脉管壁明显增厚,管腔狭窄,WT%、WA%显著升高(P<0.01)。与M4组相比,R2p组、R10p组中mRVP、mPAP、RV/( LV+S)、WT%、WA%均明显下降(P<0.05),以R10p组下降更明显,与R2p组比较差异有统计学意义(P<0.05),但均未恢复到N4组水平(P<0.01)。治疗组结果与预防组类似。
3肺小动脉BMPR-Ⅱ蛋白表达:N4组BMPR-Ⅱ蛋白大量表达,M4组表达显著下降(P<0.01);R2p组、R10p组表达较M4组不同程度升高(P<0.05),剂量间有统计学差异(P<0.05),但均未恢复到N4组水平(P<0.01)。治疗组结果与预防组类似。
4肺组织BMPR-Ⅱ蛋白、Smad4蛋白的表达量:N4组BMPR-Ⅱ蛋白、Smad4蛋白表达量较多,M4组表达量显著减少(P<0.01);R2p组、R10p组表达量较M4组有不同程度增加(P<0.05),剂量间有统计学差异(P<0.05),但均未恢复到N4组水平(P<0.01)。治疗组结果与预防组类似。
结论
野百合碱可诱导大鼠肺小动脉平滑肌增生和肥厚、肺小血管重构和右心室肥厚,形成肺动脉高压;瑞苏伐他汀可延缓野百合碱诱导的肺动脉高压的形成和缓解已经形成的肺动脉高压,减轻右室肥厚,这一机制可能是通过上升肺小动脉BMPR-Ⅱ、Smad4蛋白的表达实现的。
Objectives:
To explore the effect of morphogentic protein receptor-II signal transduction in the pathogenesis of monocrotaline-induced pulmonary hypertension in rat, and the preventive and therapeutic effects of rosuvastatin on model of PAH.
Methods:
Rats received a single subcutaneous injection of monocrotaline(MCT,50 mg/kg), to induces pulmonary arterial hypertension. Normal control rats were just injected with saline .Rats received prevention and treatmen with rosuvastatin before and after development of pulmonary arterial hypertension. In the prevention protocol:32 male Sprague-Dawley rats were randomly divided into four groups: normal control group (4 weeks) (N4),model control group(4 weeks)(M4), low-dose rosuvastatin prevention group(2mg/kg/d,R2p),high-dose rosuvastatin prevention group(10mg/kg/d,R10p). From the day MCT injection on, rats in R2p and R10p groups were prevented with rosuvastatin by daily gavage for 4 weeks. rats in N4 and M4 groups just received vehicle by gavage. In the treatment protocol:48 male Sprague-Dawley rats were randomly divided into four groups: normal control group(N8,n=8),pulmonary arterial hypertension group(M8,n=16),low-dose rosuvastatin treatment group(2mg/kg/d, R2t,n=12),high-dose rosuvastatin treatment group(10mg/kg/d,R10t,n=12);Four weeks after MCT injection, rats in R2t and R10t groups were treated with rosuvastatin by daily gavage for 4 weeks . rats in N8 and M8 groups just received vehicle by gavage. state and death were observed. When the prevention and treatment ended,polyethylene catheters were inserted into the RV through the jugular vein for hemodynamic measurements. Mean right ventricular pressure(mRVP) and mean pulmonary artery pressure(mPAP) were measured with a polygraph system.RV hypertrophy index[RV/ (LV+S)] was also measured. Arteries of 50 to 150μm were evaluated for the median wall thickness and wall area by HE staining as follows: percent wall thickness(WT%)= [(medial thickness×2/external diameter)]×100 and percent wall area (WT%)= (wall area / total area)×100. The level of BMPR-II protein expression in pulmonary artery were assessed by immunohistochemistry. Western blot was used to assess Changes of BMPR-II and Smad4 protein expression in lung tissue.
Results:
1 state and survival analysis:At 4 th weekend,all rats in the prevention protocol survived.At 8 th weekend,survival rates of N8、M8、R2t and R10t group were 100%、25%、58.3%、75% in the treatment protocol. Compared with M8 group, the survival rate of R2t and R10t group were also markedly increased(P<0.05)
2 Hemodynamics,pulmonary vascular morphology and right ventricular hypertrophy assessment: compared with N4 group,M4 group rats exhibited higher mRVP , mPAP and RV/ (LV+S) (P<0.01), arteriole endomembrane ,medial thickness,WT% and WA% were also markedly increased(P<0.01). Compared with M4 group ,R2p and R10p groups exhibited lower mRVP、mPAP、RV/ (LV+S)、WT% and WA% (P<0.05),and have statistical difference between doses(P<0.05),but have statistical difference compared with N4 group(P<0.01). The results in the treatment protocol were similar to those in the prevention protocol.
3 BMPR-II protein expression in small pulmonary artery: compared to N4 group,the expression of BMPR-II protein markedly decreased in M4 group(P<0.01);it increased in R2p and R10p groups compared to M4 group(P<0.05); and have statistical difference between doses(P<0.05),but have statistical difference compared with N4 group(P<0.01). The results in the treatment protocol were similar to those in the prevention protocol.
4 BMPR-II and Smad4 protein expressions in lung tissue: compared to N4 group,the expression of BMPR-II protein and Smad4 protein markedly decreased in M4 group(P<0.01);it increased in R2p and R10p groups compared to M4 group(P<0.05); and have statistical difference between doses(P<0.05),but have statistical difference compared with N4 group(P<0.01). The results in the treatment protocol were similar to those in the prevention protocol.
Conclusion:
MCT induced proliferation of pulmonary VSMC、pulmonary artery remodeling and RV hypertrophy in rats. Rosuvastatin lowered pulmonary artery hypertension, decreased right ventricular hypertrophy. The mechanisms of preventive and therapeutic effects of rosuvastatin on monocrotaline-induced pulmonary arterial hypertension may be contributed to up-regulate the expression of BMPR-II and Smad4 protein in lung tissue.
引文
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6 Wong GA,Tang V ,El-Sabeawy F,et al.B MP-2 inhibits proliferation of human aortic smooth muscle cells via p21 [J].Am J Physiol Endocriol Metab,2003,284(5):E972-E979.
7 Imamura T,Takase M ,Nishihara A,et a1.Smad6 inhibits signaling by the TGF—super family.Nature,1997,389:622—626.
8 Yu PB,Beppu H,Kawai N,et al. Bone morphogenetic Protein(BMP)type ll receptor deletino reveals BMP ligand-specific gain of signalling in Pulmonary artery smooth muscle cells. Jbiol Chem.2005,280(26):24443一50
9 Newman J,Wheeler L,Lane KB,et al. Mutation in the gene for bone morphogenetic protein receptor II as a cause of primary pulmonary hypertension in large kindred. N.Engl.J.Mde.2001,345:31-9324.
10James W,Karen F,Wolfgang S,et a1.Pulmonary hypertension in transgenic mice expressing a dominant—negative BMPR II gene in smooth muscle.Circ Res,2004,94:11O9—1114.
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1.Deng Z,Morse JH,Slager SL,et 81.Familial primary pulmonary hypertension(gene PPH1)is caused by mutations in the bone morphogenetic protein receptor II gene.Am J Hum Genet,2000,67:737-744.
2.Lane KB, Machado RD,Pauciulo MW ,et al. Heterozygous germline mutations in BMPR2 encoding a TGF—beta receptor,cause familial primary pulmonary hypertension. The International PPH Consortium. Nat Genet,2000,26:81-84.
3. Miyazono K.Kusanagi K,Inoue H,et a1.Divergence and convergence of TGF—beta/BMP signaling.J Cell Phyisol,2001,187:265—276.
4.Celeste AJ.Iannazzi JA,Taylor RC,et a1.Identification of transforming growth factor h family members present in bone inductive protein purified from bovine bone.Proc Natl Acad Sci USA ,1990,87:9843—9847.
5.Spinella-JaegleS ,Roman-Roman S ,Faucheu C ,et al.Opposite effects of bone morphogenetic protein-2 and transforming growth factor beta 1 on osteoblast differentiation[J].Bone , 2001,29(4):323-330.
6 Wong GA,Tang V ,El-Sabeawy F,et al.B MP-2 inhibits proliferation of human aortic smooth muscle cells via p21 [J].Am J Physiol Endocriol Metab,2003,284(5):E972-E979.
7 Imamura T,Takase M ,Nishihara A,et a1.Smad6 inhibits signaling by the TGF—super family.Nature,1997,389:622—626.
8 Yu PB,Beppu H,Kawai N,et al. Bone morphogenetic Protein(BMP)type ll receptor deletino reveals BMP ligand-specific gain of signalling in Pulmonary artery smooth muscle cells. Jbiol Chem.2005,280(26):24443一50
9 Newman J,Wheeler L,Lane KB,et al. Mutation in the gene for bone morphogenetic protein receptor II as a cause of primary pulmonary hypertension in large kindred. N.Engl.J.Mde.2001,345:31-9324.
10James W,Karen F,Wolfgang S,et a1.Pulmonary hypertension in transgenic mice expressing a dominant—negative BMPR II gene in smooth muscle.Circ Res,2004,94:11O9—1114.
11 Yang X,Long L,Southwood M ,et a1.Dysfunctional Smad signalling contributes to abnormal smooth muscle cell proliferation infamilial pulmonary arterial hypertension Cire Res,2005,96:1053—1063.
12 Morrell NW,Yang X,Upton PD ,et a1. Altered growth responses of pulmonary artery smooth muscle cells from patients with primarypulmonary hypertension to transforming growth factor-βl and bone morphogenetic proteins.Circulation,2001,104:790—795.
13 Shen Zhang,Ivana Fantozzi,Donna D,et a1.Bone morphogenetic proteins induce apoptosis in human pulmonary vascular smooth muscle cells.Am J Physiol Lung Cell Mol Physiol,2003,285:L74O—L754.
14.WestJ,Fagan K,Steudel W,et al. Pulmonary hypertension in transgenic mice expressing a dominant-negative BMPR-II gene in smooth muscle[J]. Circ Res, 2004, 94(8),1109-1114.
15 Teichert-Kuliszewska K, Kutryk MJ, Kuliszewski MA, et al. Bone morphogenetic protein receptor-2 signaling promotes pulmonary raterial endothelial cell survival: implications for loss-of-function mutations in the pathogenesis of pulmonary hypertension [ J〕.Circ Res, 2006, 98(2) 209-217.
16.Sakso S,Taraseviciene-StewartL ,Lee JD,et al. Initial apoptosisis followed by increased proliferation of apoptosis resistant endothelial cells[J].F ASEBJ,2 005,1 9(9):1178-1180.
17 Weir EK,Lopez-Barneo ,BucklerK J,et al.Acute oxygensensing mechanisms[J]. N EnglJ M ed,2005,3 53(15); 2042- 2055.
18 Newman JH,Trembath RC,Morse JA,et al. Genetic basis of pulmonary arterial hypertension;current understanding and future directions[J].J Am Coll Cardiol,2004,43(12 Suppls) :33S-39S.
19 Foletta VC,Lim MA,Soosariajah J ,et al. Direct signaling by the BMP type II receptor via hecytoskeletal regulator LIMK1[J].J Cell Biol,2003,162(6):1089-1098.
20 Du L ,Sullivan CC,Chu D ,et al. Signaling molecules in non-familial pulmonary hypertension[ J] . N Engl J Med, 2003,348(6):500-509.
21 Long L,MacLean MR,Jefery TK,et al Serotonin increases susceptibility Pulmonary hypertension in BMPR2一deficient mice.Circ Res,2006,to98(6):818-27