• 1 解放軍總醫(yī)院國(guó)際醫(yī)學(xué)中心( 北京 100853) ;;
  • 2 中國(guó)醫(yī)學(xué)科學(xué)院中國(guó)協(xié)和醫(yī)科大學(xué)北京協(xié)和醫(yī)院呼吸內(nèi)科( 北京 100730) ;;
  • 3 北京積水潭醫(yī)院呼吸內(nèi)科( 北京 100035)通訊作者: 張偉華, E-mail: whuazhang@ 126. com;

目的  觀察辛伐他汀對(duì)野百合堿致肺動(dòng)脈高壓大鼠的肺循環(huán)血流動(dòng)力學(xué)和肺小動(dòng)脈重構(gòu)的作用, 以及對(duì)肺組織血紅素加氧酶1( HO-1) 表達(dá)的影響。方法  52 只SD 大鼠隨機(jī)分為五組:正常對(duì)照組、辛伐他汀對(duì)照組、肺動(dòng)脈高壓模型組、辛伐他汀治療組和血紅素加氧酶抑制劑( ZnPP)組。右心導(dǎo)管測(cè)定肺動(dòng)脈平均壓( mPAP) 、右心室收縮壓( RVSP) 。以右心室/ ( 左心室+ 室間隔) 的質(zhì)量比( RVHI) 作為評(píng)價(jià)右心室肥厚的指標(biāo)。病理圖像分析系統(tǒng)測(cè)定并計(jì)算動(dòng)脈管壁面積百分比和動(dòng)脈管壁直徑百分比以評(píng)價(jià)肺血管重構(gòu)嚴(yán)重程度。免疫組化方法觀察HO-1 在大鼠肺組織中表達(dá)部位, 通過(guò)免疫印跡法半定量測(cè)定肺組織HO-1 蛋白表達(dá)水平。結(jié)果  與模型組比較, 辛伐他汀治療組mPAP、RVHI 顯著降低[ ( 35. 63 ±5. 10) mmHg 比( 65. 78 ±15. 51) mm Hg, 0. 33 ±0. 05 比0. 53 ±0. 06, P  lt;0. 05] 。辛伐他汀治療減輕了肺血管重構(gòu), 動(dòng)脈管壁面積百分比和動(dòng)脈管壁直徑百分比分
別為( 50. 78 ±9. 03) % 和( 43. 75 ±4. 23) % , 較模型組明顯降低[ ( 65. 92 ±7. 19) % , ( 52. 00 ±5. 35) % ] 。免疫組化顯示在肺動(dòng)脈高壓模型組, HO-1 主要在肺泡巨噬細(xì)胞中呈陽(yáng)性表達(dá)。在辛伐他汀治療組, HO-1 表達(dá)明顯增高, 尤其在血管平滑肌細(xì)胞和肺泡巨噬細(xì)胞呈強(qiáng)陽(yáng)性表達(dá)。HO-1 的抑制劑ZnPP部分抑制辛伐他汀對(duì)PH 大鼠的作用, 其mPAP 為( 52. 88 ±17. 45) mmHg, 動(dòng)脈管壁面積% 為( 50. 78 ±9. 03) % , 動(dòng)脈管壁直徑百分比為( 52. 00 ±5. 35) 百分比。結(jié)論  辛伐他汀減輕野百合堿誘導(dǎo)大鼠的肺動(dòng)脈高壓, 抑制肺血管重構(gòu)改變, 其作用機(jī)制與增加HO-1 表達(dá)有關(guān)。

引用本文： 張偉華,陸慰萱,張運(yùn)劍,余秉翔. 辛伐他汀對(duì)野百合堿誘導(dǎo)肺動(dòng)脈高壓大鼠血紅素加氧酶1 表達(dá)的影響. 中國(guó)呼吸與危重監(jiān)護(hù)雜志, 2010, 9(5): 523-527. doi: 復(fù)制

1. Runo JR, Loyd JE. Primary pulmonary hypertension. Lancet, 2003 ,361: 1533-1544.
2. Kao PN, Faul JL. Emerging therapies for pulmonary hypertension:striving for effecicacy and safety. J Am Coll Cardiol, 2003, 41 : 2126 -2129.
3. Newman JH, Lane KB. Hypertension pulmonary vascular disease:dawn of the age of prevention? Am J Respir Crit Care Med, 2000 ,162: 2020-2021.
4. Rubin LJ. Primary pulmonary hypertension: pathophysiology and clinical aspects. Pulmonary circulation: diseases and their treatment. 166-171 . Edited by Peacock AJ & Rubin LJ.
5. Murata M, Kinoshita K, Hori M et al. Statin protects endothelial nitric oxide synthase activity in hypoxia-induced pulmonary hypertension. Arterioscler Thromb Vasc Biol, 2005, 25: 2335 -2342 .
6. Girgis RE, Li D, Zhan XH et al. Attenuation of chronic hypoxic pulmonary hypertension by simvastatin. Am J Physiol Heart Cric Physiol, 2003 , 285: H938 -H945.
7. Nishimura T, Faul JL, Berry GJ, et al. Simvastatin attenuates smooth muscle neointimal proliferation and pulmonary hypertension in rats.Am J Respir Crit Care Med, 2002, 166: 1403-1408.
8. Guerard P, Rakotoniaina Z, Goirand F, et al. The HMG-CoA reductase inhibitor, pravastatin, prevents the development of monocrotaline-induced pulmonary hypertension in the rat through reduction of endothelial cell apoptosis and overexpression of eNOS.Nauyn-chmiedeberg’s Arch Pharmacol, 2006, 373 : 401-414.
9. Shibahara S, Kitamuro T, Takahashi K. Heme degration and human disease: diversity is the sole of life. Antioxid Redox Signal, 2002, 4 :593 -602.
10. Lalich JJ, Merkow L. Pulmonary arteries produced in rats by feeding crotolaria spectabilis. Lab Invest, 1961, 10 : 744-750.
11. Nishmura T, Vaszar LT, Faul JL. Simvastatin rescues from fatal pulmonary hypertension by inducing apoptosis of neointimal smooth muscle cells. Circulation, 2003, 108: 1640-1645.
12. Wilks A. Heme oxygenase: evaluation, structure, and mechanism.Antioxide Redox Signal, 2002, 4: 603-614 .
13. Peterson SJ, Frishman WH, Abraham NG. Targeting heme oxygenase: therapeutic implications for diseases of the cardiovascular system. Cardiol Rev, 2009 , 17: 99-111 .
14. Yet SF, Perrella MA, Layne MD, et al. Hypoxia induces severe right ventricular dilatation and infarction in heme oxygenase-1 null mice.J Clin Invest, 1999, 103: R23-R29.
15. Minamion T, Christou H, Hsieh CM, et al. Targeted expression of heme oxygenase-1 prevents the pulmonary inflammatory and vascular responses to hypoxia. Proc Nat Acad Sci USA, 2001, 98 : 8798 -8803.
16. Vitali SH, Mitsialis SA, Christou H, et al. Mechanisms of heme oxygenase-1-mediated cardiac and pulmonary vascular protection in chronic hypoxia. Chest, 2005, 128: 578S-579S.
17. Lee TS, Chang CC, Zhu Y et al. Simvastatin induces heme oxygenase-1: a novel mechanism of vessel protection. Circulation,2004, 7, 110 : 1296 -1302 .
18. Grosser N, Hemmerle A, Berndt G et al. The antioxidant defense protein heme oxygenase 1 is a novel target for statins in endothelial cells. Free Radic Biol Med, 2004, 15 , 37: 2064-2071.
  1. 1. Runo JR, Loyd JE. Primary pulmonary hypertension. Lancet, 2003 ,361: 1533-1544.
  2. 2. Kao PN, Faul JL. Emerging therapies for pulmonary hypertension:striving for effecicacy and safety. J Am Coll Cardiol, 2003, 41 : 2126 -2129.
  3. 3. Newman JH, Lane KB. Hypertension pulmonary vascular disease:dawn of the age of prevention? Am J Respir Crit Care Med, 2000 ,162: 2020-2021.
  4. 4. Rubin LJ. Primary pulmonary hypertension: pathophysiology and clinical aspects. Pulmonary circulation: diseases and their treatment. 166-171 . Edited by Peacock AJ & Rubin LJ.
  5. 5. Murata M, Kinoshita K, Hori M et al. Statin protects endothelial nitric oxide synthase activity in hypoxia-induced pulmonary hypertension. Arterioscler Thromb Vasc Biol, 2005, 25: 2335 -2342 .
  6. 6. Girgis RE, Li D, Zhan XH et al. Attenuation of chronic hypoxic pulmonary hypertension by simvastatin. Am J Physiol Heart Cric Physiol, 2003 , 285: H938 -H945.
  7. 7. Nishimura T, Faul JL, Berry GJ, et al. Simvastatin attenuates smooth muscle neointimal proliferation and pulmonary hypertension in rats.Am J Respir Crit Care Med, 2002, 166: 1403-1408.
  8. 8. Guerard P, Rakotoniaina Z, Goirand F, et al. The HMG-CoA reductase inhibitor, pravastatin, prevents the development of monocrotaline-induced pulmonary hypertension in the rat through reduction of endothelial cell apoptosis and overexpression of eNOS.Nauyn-chmiedeberg’s Arch Pharmacol, 2006, 373 : 401-414.
  9. 9. Shibahara S, Kitamuro T, Takahashi K. Heme degration and human disease: diversity is the sole of life. Antioxid Redox Signal, 2002, 4 :593 -602.
  10. 10. Lalich JJ, Merkow L. Pulmonary arteries produced in rats by feeding crotolaria spectabilis. Lab Invest, 1961, 10 : 744-750.
  11. 11. Nishmura T, Vaszar LT, Faul JL. Simvastatin rescues from fatal pulmonary hypertension by inducing apoptosis of neointimal smooth muscle cells. Circulation, 2003, 108: 1640-1645.
  12. 12. Wilks A. Heme oxygenase: evaluation, structure, and mechanism.Antioxide Redox Signal, 2002, 4: 603-614 .
  13. 13. Peterson SJ, Frishman WH, Abraham NG. Targeting heme oxygenase: therapeutic implications for diseases of the cardiovascular system. Cardiol Rev, 2009 , 17: 99-111 .
  14. 14. Yet SF, Perrella MA, Layne MD, et al. Hypoxia induces severe right ventricular dilatation and infarction in heme oxygenase-1 null mice.J Clin Invest, 1999, 103: R23-R29.
  15. 15. Minamion T, Christou H, Hsieh CM, et al. Targeted expression of heme oxygenase-1 prevents the pulmonary inflammatory and vascular responses to hypoxia. Proc Nat Acad Sci USA, 2001, 98 : 8798 -8803.
  16. 16. Vitali SH, Mitsialis SA, Christou H, et al. Mechanisms of heme oxygenase-1-mediated cardiac and pulmonary vascular protection in chronic hypoxia. Chest, 2005, 128: 578S-579S.
  17. 17. Lee TS, Chang CC, Zhu Y et al. Simvastatin induces heme oxygenase-1: a novel mechanism of vessel protection. Circulation,2004, 7, 110 : 1296 -1302 .
  18. 18. Grosser N, Hemmerle A, Berndt G et al. The antioxidant defense protein heme oxygenase 1 is a novel target for statins in endothelial cells. Free Radic Biol Med, 2004, 15 , 37: 2064-2071.