阿托伐他汀对野百合碱诱导的大鼠肺动脉高压及肺组织NF-κB表达的影响
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摘要
目的：观察阿托伐他汀对野百合碱(MCT)诱导的肺动脉高压大鼠的影响，探讨核因子-κappaB(NF-κB)在MCT诱导的肺动脉高压发病中的作用和阿托伐他汀对MCT诱导的肺动脉高压大鼠肺组织NF-κB表达的影响。
方法：将24只健康雄性SD大鼠随机分为正常对照组(对照组)，MCT诱导的肺动脉高压组(MCT组)，阿托伐他汀干预组(AS组)，每组8只。MCT组和AS组分别一次性腹部皮下注射MCT(60mg／kg)，对照组以等量生理盐水代替。AS组自注射MCT之日起以阿托伐他汀(10mg／kg)灌胃，每日一次。MCT组以生理盐水(10ml／kg)每日灌胃。3周后达实验终点，测定大鼠平均肺动脉压(mPAP)、平均颈动脉压(mCAP)，计算右心室肥大指数(RVHI)。肺组织切片进行苏木素-伊红(HE)染色，光镜下观察肺组织形态学的改变，并计算肺中小动脉管壁厚度占血管外径的百分比(WT％)和肺动脉管壁面积／管总面积的百分比(WA％)，以此反映肺血管重建情况。采用免疫组化法观察大鼠肺组织NF-κB表达的变化。
结果：
1．MCT组大鼠的mPAP和RVHI均显著高于对照组(P＜0.01)，而AS组大鼠的mPAP和RVHI均较MCT组明显降低(P＜0.01)，但AS组大鼠的mPAP和RVHI均较对照组明显增高(P＜0.05)。三组大鼠的mCAP没有明显差别(P均＞0.05)。
2．对照组大鼠肺中小动脉管壁薄，管腔大；MCT组大鼠肺中小动脉，管壁厚度明显增加，管腔面积明显变小，伴有明显的血管周围炎；AS组大鼠肺中小动脉管壁厚度较MCT组明显减小，管腔面积较MCT组明显增大，血管周围炎明显减轻。
3．MCT组大鼠肺中小动脉WT％和WA％均明显高于对照组(P)＜0.01)，AS组大鼠肺中小动脉WT％和WA％均明显低于MCT组(P＜0.01)，但AS组大鼠肺中小动脉WT％和WA％均明显高于对照组(P＜0.01)。
4．大鼠细支气管上皮细胞NF-κB核阳性细胞百分比：MCT组明显高于对照组(P＜0.01)，AS组明显低于MCT组(P＜0.01)，但明显高于对照组(P＜0.01)。
5．大鼠细支气管上皮细胞NF-κB核阳性细胞百分比与mPAP、肺中小动脉WT％和WA％成明显正相关(P均＜0.01)。
结论：阿托伐他汀可降低MCT所致的肺组织NF-κB的表达，具有抑制MCT诱导的肺部炎症、肺血管重建和肺动脉高压形成的作用。
Objective: To investigate the effects of atorvastatin onmonocrotaline (MCT)-induced pulmonary hypertension in rats and theexpression of nuclear factor-kappa B (NF-κB) in lung.
Methods: Twenty-four male SD rats were randomly divided intothree groups with eight rats each group: control group, MCT group andatorvastatin group (AS group). The rats in MCT and AS group were givena single subcutaneously injection of MCT (60mg/kg) and the rats incontrol group were injected with saline. Atorvastatin (10mg/kg/d) weregiven orally for 21 days to the rats in AS groups and vehicle were givento the rats in MCT group since the day when rats were injected MCT. At22 days, mean pulmonary arterial pressure (mPAP), mean carotidpressure (mCAP) and right ventricular hypertrophy index (RVHI) weremeasured. The index of wall thickness of pulmonary arteriole wasmeasured by a computerized image analyzer. The expression of NF-κB inbronchioles was observed by immunohistochemistry.
Results:
1. The mPAP and RVHI were increased significantly in MCT groupthan that in control group (P＜0.01). This increase in mPAP and RVHI was partially prevented by atorvastatin(P＜0.01). There was no significantdiscrepancy on mCAP between three groups (P＞0.05).
2. The thickness of the medial wall of pulmonary medial arteries andarteriole was significantly increased in MCT group as compared withcontrol group. Large numbers inflammatory cells congregated around thesmall vascular and in the pulmonary interstitial in MCT group.Atorvastatin treatment was associated with a significant reduction ofMCT-induced thickening and the number of inflammatory cells.
3. WT％and WA％of pulmonary medial arteries and arteriole wereincreased significantly in MCT group than that in control group (P＜0.01).This increase in WT％and WA％was partially prevented by atorvastatin(P＜0.01).
4. The percentage of positive cells for NF-κB nuclear staining inbronchiolar epithelial cells was significantly increased in MCT groupthan that in the control group (P＜0.01), but in AS group, it wassignificantly decreased than that in the MCT group(P＜0.01).
5. The percentage of positive cells for NF-κB nuclear staining inbronchiolar epithelial cells was positively correlated with mPAP andWT％and WA％of pulmonary medial arteries and arteriole(P＜0.01,respectively).
Conclusions: Atorvastatin could reduce NF-κB expression ofbronchiolar induced by MCT, prevent MCT-induced inflammatory response, pulmonary vascular remodeling and the development ofpulmonary hypertension.
方法：将24只健康雄性SD大鼠随机分为正常对照组(对照组)，MCT诱导的肺动脉高压组(MCT组)，阿托伐他汀干预组(AS组)，每组8只。MCT组和AS组分别一次性腹部皮下注射MCT(60mg／kg)，对照组以等量生理盐水代替。AS组自注射MCT之日起以阿托伐他汀(10mg／kg)灌胃，每日一次。MCT组以生理盐水(10ml／kg)每日灌胃。3周后达实验终点，测定大鼠平均肺动脉压(mPAP)、平均颈动脉压(mCAP)，计算右心室肥大指数(RVHI)。肺组织切片进行苏木素-伊红(HE)染色，光镜下观察肺组织形态学的改变，并计算肺中小动脉管壁厚度占血管外径的百分比(WT％)和肺动脉管壁面积／管总面积的百分比(WA％)，以此反映肺血管重建情况。采用免疫组化法观察大鼠肺组织NF-κB表达的变化。
结果：
1．MCT组大鼠的mPAP和RVHI均显著高于对照组(P＜0.01)，而AS组大鼠的mPAP和RVHI均较MCT组明显降低(P＜0.01)，但AS组大鼠的mPAP和RVHI均较对照组明显增高(P＜0.05)。三组大鼠的mCAP没有明显差别(P均＞0.05)。
2．对照组大鼠肺中小动脉管壁薄，管腔大；MCT组大鼠肺中小动脉，管壁厚度明显增加，管腔面积明显变小，伴有明显的血管周围炎；AS组大鼠肺中小动脉管壁厚度较MCT组明显减小，管腔面积较MCT组明显增大，血管周围炎明显减轻。
3．MCT组大鼠肺中小动脉WT％和WA％均明显高于对照组(P)＜0.01)，AS组大鼠肺中小动脉WT％和WA％均明显低于MCT组(P＜0.01)，但AS组大鼠肺中小动脉WT％和WA％均明显高于对照组(P＜0.01)。
4．大鼠细支气管上皮细胞NF-κB核阳性细胞百分比：MCT组明显高于对照组(P＜0.01)，AS组明显低于MCT组(P＜0.01)，但明显高于对照组(P＜0.01)。
5．大鼠细支气管上皮细胞NF-κB核阳性细胞百分比与mPAP、肺中小动脉WT％和WA％成明显正相关(P均＜0.01)。
结论：阿托伐他汀可降低MCT所致的肺组织NF-κB的表达，具有抑制MCT诱导的肺部炎症、肺血管重建和肺动脉高压形成的作用。
Objective: To investigate the effects of atorvastatin onmonocrotaline (MCT)-induced pulmonary hypertension in rats and theexpression of nuclear factor-kappa B (NF-κB) in lung.
Methods: Twenty-four male SD rats were randomly divided intothree groups with eight rats each group: control group, MCT group andatorvastatin group (AS group). The rats in MCT and AS group were givena single subcutaneously injection of MCT (60mg/kg) and the rats incontrol group were injected with saline. Atorvastatin (10mg/kg/d) weregiven orally for 21 days to the rats in AS groups and vehicle were givento the rats in MCT group since the day when rats were injected MCT. At22 days, mean pulmonary arterial pressure (mPAP), mean carotidpressure (mCAP) and right ventricular hypertrophy index (RVHI) weremeasured. The index of wall thickness of pulmonary arteriole wasmeasured by a computerized image analyzer. The expression of NF-κB inbronchioles was observed by immunohistochemistry.
Results:
1. The mPAP and RVHI were increased significantly in MCT groupthan that in control group (P＜0.01). This increase in mPAP and RVHI was partially prevented by atorvastatin(P＜0.01). There was no significantdiscrepancy on mCAP between three groups (P＞0.05).
2. The thickness of the medial wall of pulmonary medial arteries andarteriole was significantly increased in MCT group as compared withcontrol group. Large numbers inflammatory cells congregated around thesmall vascular and in the pulmonary interstitial in MCT group.Atorvastatin treatment was associated with a significant reduction ofMCT-induced thickening and the number of inflammatory cells.
3. WT％and WA％of pulmonary medial arteries and arteriole wereincreased significantly in MCT group than that in control group (P＜0.01).This increase in WT％and WA％was partially prevented by atorvastatin(P＜0.01).
4. The percentage of positive cells for NF-κB nuclear staining inbronchiolar epithelial cells was significantly increased in MCT groupthan that in the control group (P＜0.01), but in AS group, it wassignificantly decreased than that in the MCT group(P＜0.01).
5. The percentage of positive cells for NF-κB nuclear staining inbronchiolar epithelial cells was positively correlated with mPAP andWT％and WA％of pulmonary medial arteries and arteriole(P＜0.01,respectively).
Conclusions: Atorvastatin could reduce NF-κB expression ofbronchiolar induced by MCT, prevent MCT-induced inflammatory response, pulmonary vascular remodeling and the development ofpulmonary hypertension.
引文
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[1] Vincent L, Chen W, Hong L, et al. Inhibition of endothelial cell migration.by cerivastatin, an HMG-CoA reductase inhibitor: contribution to its anti-angiogenic effect. FEBS Lett, 2001,495(3): 159-66.
[2] Laufs U, Marra D, Node K, et al. 3-Hydroxy-3-methylglutaryl-CoA reductase inhib- itors attenuate vascular smooth muscle proliferation by preventing Rho GTPase-induced down-regulation of p27(Kip1). J Biol Chem, 1999,274 (31):21926-31.
[3] Rao S, Porter DC, Chen X, et al. Lovastatin-mediated G1 arrest is through inhibition of the proteasome, independent of hydroxymethyl glutaryl-CoA reductase. Proc Natl Acad Sci U S A, 1999,96(14):7797-802.
[4] Vidal A, Millard SS, Miller JP, et al. Rho activity can alter the translation of p27 mRNA and is important for RasV12-induced transformation in a manner dependent on p27 status. J Biol Chem, 2002,277(19): 16433-40.
[5] Sindermann JR, Fan L, Weigle KA, et al. Differences in the effects of the HMGCoA reductase inhibitors on proliferation and viability of smooth muscle cells in culture. Atherosclerosis, 2000,150(2):331-41.
[6] 单江，程刚，傅国胜，等．普伐他汀抑制血管平滑肌细胞增殖及对PTEN，P27蛋白表达的影响．中华心血管病杂志，2002，30(10)：622-5．
[7] Fouty BW, Rodman DM. Mevastatin can cause G1 arrest and induce apoptosis in pulmonary, artery smooth muscle cells-through a p27Kipl-independent pathway. Circ Res, 2003,92(5):501-9.
[8] Toshihiko N, Laszlo TV. Simvastatin rescues rats from fatal pulmonary hypertension by inducing apoptosis of neointimal smooth muscle cells. Circulation, 2003,108 (13): 1640-5.
[9] Cheng G, Shan J, Xu G, et al. Apoptosis induced by simvastatin in rat vascular smooth muscle cell through Ca~(2+) -calpain and caspase-3 dependent pathway. Pharmacolo Res, 2003,48(6):571-8.
[10] Wilson SH, Herrmann J, Lerman LO, et al. Simvastatin preserves the structure of coronary adventitial vasa vasorum in experimental hypercholsterolemia independent of lipid lowering. Circulation, 2002,105(4):415-8.
[11] Schafer M, Schafer C, Ewald N, et al. Role of redox signaling in the autonomous proliferative response of endothelial cells to hypoxia. Circ Res, 2003,92(9): 1010- 5.
[12] Christian AS, Christoph RW, Sebastian W, et al. Statins inhibit hypoxia-induced endothelial proliferation by preventing calcium-induced ROS formation. Atherosclerosis, 2006,185(2):290-6.
[13] Shigeru K, Kumi S, Seiichiro K, et al. All hydrophobic HMG-CoA reductase inhibitors induce apoptotic death in rat pulmonary vein endothelial cells. Atherosclerosis, 2003,70(2):237-43.
[14] Mueck AO, Seeger H, Wallwiener D, et al. Further evidence for direct vascular actions of statins: effect on endothelial nitric oxide synthase and adhesion molecules. Exp Clin Endocrinol Diabetes, 2001,109(3): 181-3.
[15] Kureishi Y, Luo Z, Shiojima I, et al. The HMG-CoA reductase inhibitor simvastatin activates the protein kinase Akt and promotes angiogenesis innormocholesterolemic animals. Nat Med, 2000,6(9): 1004-10.
[16] Laufs U, Endres M, Stagliano N, et al. Neuroprotection mediated by changes in the endothelial actin cytoskeleton. J Clin Invest, 2000,106(1): 15-24.
[17] Nishimura T, Faul JL, Berry GJ, et al. Simvastatin attenuates smooth muscle neoint- imal proliferation and pulmonary hypertension in rats. Am J Respir Crit Care Med, 2002,166(10): 1403-8.
[18] Lee JH, Lee DS, Kim EK, et al. Simvastatin inhibits cigarette smoking-induced em- physema and pulmonary hypertension in rat lungs. Am J Respir Crit Care Med, 2005,172(8):987-93.
[19] Takahisa M, Kazuya K, Masatoshi H, et al. Statin protects endothelial nitric oxide synthase activity in hypoxia-induced pulmonary hypertension. Arterioscler Thromb Vasc Biol, 2005,25(11):2335-42.
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[21] Degraeve F, Bolla M, Blaie S, et al. Modulation of COX-2 expression by statins in human aortic smooth muscle, cells. Involvement of geranylgeranylated proteins. J Biol Chem, 2001,276(50):46849-55.
[22] Mraiche F, Cena. J, Das D, et al. Effects of statins on vascular function of endothelin-1. Br J Pharmacol, 2005,144(5):715-26.
[23] Hernandez PO, Perez SD, Soria E, et al. Involvement of Rho GTPases in the transcr- iptional inhibition of preproendothelin-1 gene expression by simvastatin in vascular endothelial cells. Circ Res, 2000,87(7):616-22.
[24] Lee SD, Lee JH, Kim EK, et al. Effects of simvastatin on cigarette. smoking-induced structural and functional changes in rat lungs. Chest, 2005,128(6 Suppl):574S.
[25] Reda EG, Dechun L, Xinhua Zh, et al. Attenuation of chronic hypoxic pulmonary hypertension by simvastatin. Am J Physiol Heart Circ Physiol, 2003,285(3):938-45.
[26] Arai A, Kanda E, Miura O. Rae is activated by erythropoietin or interleukin-3 and is involved in activation of the Erk signaling pathway. Oncogene, 2002,21 (17):2641-51.
[27] Girgis RE, Mozammel S, Champion HC, et al. Regression of Chronic Hypoxic Pulmonary Hypertension by Simvastatin. Am J Physiol Lung Cell Mol Physiol, 2007. (In press)
[28] Souza-Costa DC, Figueiredo-Lopes L, Alves-Filho JC, et al. Protective effects of atorvastatin in rat models of acute pulmonary embolism: involvement of matrix metalloproteinase-9. Crit Care Med, 2007,35(1):239-45.
[29] 潘殿柱，李永春．阿托伐他汀对低氧大鼠肺血管重建的影响．中国全科医学，2005，14(14)：1149-51．
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[1] Vincent L, Chen W, Hong L, et al. Inhibition of endothelial cell migration.by cerivastatin, an HMG-CoA reductase inhibitor: contribution to its anti-angiogenic effect. FEBS Lett, 2001,495(3): 159-66.
[2] Laufs U, Marra D, Node K, et al. 3-Hydroxy-3-methylglutaryl-CoA reductase inhib- itors attenuate vascular smooth muscle proliferation by preventing Rho GTPase-induced down-regulation of p27(Kip1). J Biol Chem, 1999,274 (31):21926-31.
[3] Rao S, Porter DC, Chen X, et al. Lovastatin-mediated G1 arrest is through inhibition of the proteasome, independent of hydroxymethyl glutaryl-CoA reductase. Proc Natl Acad Sci U S A, 1999,96(14):7797-802.
[4] Vidal A, Millard SS, Miller JP, et al. Rho activity can alter the translation of p27 mRNA and is important for RasV12-induced transformation in a manner dependent on p27 status. J Biol Chem, 2002,277(19): 16433-40.
[5] Sindermann JR, Fan L, Weigle KA, et al. Differences in the effects of the HMGCoA reductase inhibitors on proliferation and viability of smooth muscle cells in culture. Atherosclerosis, 2000,150(2):331-41.
[6] 单江，程刚，傅国胜，等．普伐他汀抑制血管平滑肌细胞增殖及对PTEN，P27蛋白表达的影响．中华心血管病杂志，2002，30(10)：622-5．
[7] Fouty BW, Rodman DM. Mevastatin can cause G1 arrest and induce apoptosis in pulmonary, artery smooth muscle cells-through a p27Kipl-independent pathway. Circ Res, 2003,92(5):501-9.
[8] Toshihiko N, Laszlo TV. Simvastatin rescues rats from fatal pulmonary hypertension by inducing apoptosis of neointimal smooth muscle cells. Circulation, 2003,108 (13): 1640-5.
[9] Cheng G, Shan J, Xu G, et al. Apoptosis induced by simvastatin in rat vascular smooth muscle cell through Ca~(2+) -calpain and caspase-3 dependent pathway. Pharmacolo Res, 2003,48(6):571-8.
[10] Wilson SH, Herrmann J, Lerman LO, et al. Simvastatin preserves the structure of coronary adventitial vasa vasorum in experimental hypercholsterolemia independent of lipid lowering. Circulation, 2002,105(4):415-8.
[11] Schafer M, Schafer C, Ewald N, et al. Role of redox signaling in the autonomous proliferative response of endothelial cells to hypoxia. Circ Res, 2003,92(9): 1010- 5.
[12] Christian AS, Christoph RW, Sebastian W, et al. Statins inhibit hypoxia-induced endothelial proliferation by preventing calcium-induced ROS formation. Atherosclerosis, 2006,185(2):290-6.
[13] Shigeru K, Kumi S, Seiichiro K, et al. All hydrophobic HMG-CoA reductase inhibitors induce apoptotic death in rat pulmonary vein endothelial cells. Atherosclerosis, 2003,70(2):237-43.
[14] Mueck AO, Seeger H, Wallwiener D, et al. Further evidence for direct vascular actions of statins: effect on endothelial nitric oxide synthase and adhesion molecules. Exp Clin Endocrinol Diabetes, 2001,109(3): 181-3.
[15] Kureishi Y, Luo Z, Shiojima I, et al. The HMG-CoA reductase inhibitor simvastatin activates the protein kinase Akt and promotes angiogenesis innormocholesterolemic animals. Nat Med, 2000,6(9): 1004-10.
[16] Laufs U, Endres M, Stagliano N, et al. Neuroprotection mediated by changes in the endothelial actin cytoskeleton. J Clin Invest, 2000,106(1): 15-24.
[17] Nishimura T, Faul JL, Berry GJ, et al. Simvastatin attenuates smooth muscle neoint- imal proliferation and pulmonary hypertension in rats. Am J Respir Crit Care Med, 2002,166(10): 1403-8.
[18] Lee JH, Lee DS, Kim EK, et al. Simvastatin inhibits cigarette smoking-induced em- physema and pulmonary hypertension in rat lungs. Am J Respir Crit Care Med, 2005,172(8):987-93.
[19] Takahisa M, Kazuya K, Masatoshi H, et al. Statin protects endothelial nitric oxide synthase activity in hypoxia-induced pulmonary hypertension. Arterioscler Thromb Vasc Biol, 2005,25(11):2335-42.
[20] Girgis RE, Li D, Zhan X, et al. Attenuation of chronic hypoxic pulmonary hypertension by simvastatin. Am J Physiol Heart Circ Physiol, 2003, 285(3):H938-45.
[21] Degraeve F, Bolla M, Blaie S, et al. Modulation of COX-2 expression by statins in human aortic smooth muscle, cells. Involvement of geranylgeranylated proteins. J Biol Chem, 2001,276(50):46849-55.
[22] Mraiche F, Cena. J, Das D, et al. Effects of statins on vascular function of endothelin-1. Br J Pharmacol, 2005,144(5):715-26.
[23] Hernandez PO, Perez SD, Soria E, et al. Involvement of Rho GTPases in the transcr- iptional inhibition of preproendothelin-1 gene expression by simvastatin in vascular endothelial cells. Circ Res, 2000,87(7):616-22.
[24] Lee SD, Lee JH, Kim EK, et al. Effects of simvastatin on cigarette. smoking-induced structural and functional changes in rat lungs. Chest, 2005,128(6 Suppl):574S.
[25] Reda EG, Dechun L, Xinhua Zh, et al. Attenuation of chronic hypoxic pulmonary hypertension by simvastatin. Am J Physiol Heart Circ Physiol, 2003,285(3):938-45.
[26] Arai A, Kanda E, Miura O. Rae is activated by erythropoietin or interleukin-3 and is involved in activation of the Erk signaling pathway. Oncogene, 2002,21 (17):2641-51.
[27] Girgis RE, Mozammel S, Champion HC, et al. Regression of Chronic Hypoxic Pulmonary Hypertension by Simvastatin. Am J Physiol Lung Cell Mol Physiol, 2007. (In press)
[28] Souza-Costa DC, Figueiredo-Lopes L, Alves-Filho JC, et al. Protective effects of atorvastatin in rat models of acute pulmonary embolism: involvement of matrix metalloproteinase-9. Crit Care Med, 2007,35(1):239-45.
[29] 潘殿柱，李永春．阿托伐他汀对低氧大鼠肺血管重建的影响．中国全科医学，2005，14(14)：1149-51．
[30] Rakotoniaina Z, Guerard P, Lirussi F, et al. The protective effect of HMG-CoA reductase inhibitors against monocrotaline-induced pulmonary hypertension in the rat might not be a class effect: comparison of pravastatin and atorvastatin. Naunyn Schmiedebergs Arch Pharmacol, 2006,374(3): 195-206.
[31] Kao PN. Simvastatin treatment of pulmonary hypertension: an observational case series. Chest, 2005,127(4): 1446-52.