辛伐他汀對野百合堿誘導肺動脈高壓大鼠血紅素加氧酶1 表達的影響_《中國呼吸與危重監護雜志》

作者：

張偉華 ¹ , 陸慰萱 ² , 張運劍 ³ , 余秉翔 ¹

1 解放軍總醫院國際醫學中心( 北京 100853) ;;
2 中國醫學科學院中國協和醫科大學北京協和醫院呼吸內科( 北京 100730) ;;
3 北京積水潭醫院呼吸內科( 北京 100035)通訊作者: 張偉華, E-mail: whuazhang@ 126. com;

關鍵詞：

辛伐他汀肺動脈高壓血紅素加氧酶1 野百合堿

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目的觀察辛伐他汀對野百合堿致肺動脈高壓大鼠的肺循環血流動力學和肺小動脈重構的作用, 以及對肺組織血紅素加氧酶1( HO-1) 表達的影響。方法 52 只SD 大鼠隨機分為五組:正常對照組、辛伐他汀對照組、肺動脈高壓模型組、辛伐他汀治療組和血紅素加氧酶抑制劑( ZnPP)組。右心導管測定肺動脈平均壓( mPAP) 、右心室收縮壓( RVSP) 。以右心室/ ( 左心室+ 室間隔) 的質量比( RVHI) 作為評價右心室肥厚的指標。病理圖像分析系統測定并計算動脈管壁面積百分比和動脈管壁直徑百分比以評價肺血管重構嚴重程度。免疫組化方法觀察HO-1 在大鼠肺組織中表達部位, 通過免疫印跡法半定量測定肺組織HO-1 蛋白表達水平。結果與模型組比較, 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, 動脈管壁面積百分比和動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脈高壓模型組, HO-1 主要在肺泡巨噬細胞中呈陽性表達。在辛伐他汀治療組, HO-1 表達明顯增高, 尤其在血管平滑肌細胞和肺泡巨噬細胞呈強陽性表達。HO-1 的抑制劑ZnPP部分抑制辛伐他汀對PH 大鼠的作用, 其mPAP 為( 52. 88 ±17. 45) mmHg, 動脈管壁面積% 為( 50. 78 ±9. 03) % , 動脈管壁直徑百分比為( 52. 00 ±5. 35) 百分比。結論辛伐他汀減輕野百合堿誘導大鼠的肺動脈高壓, 抑制肺血管重構改變, 其作用機制與增加HO-1 表達有關。

引用本文： 張偉華,陸慰萱,張運劍,余秉翔. 辛伐他汀對野百合堿誘導肺動脈高壓大鼠血紅素加氧酶1 表達的影響. 中國呼吸與危重監護雜志, 2010, 9(5): 523-527. doi: 復制

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. 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.

《中國呼吸與危重監護雜志》

辛伐他汀對野百合堿誘導肺動脈高壓大鼠血紅素加氧酶1 表達的影響

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《中國呼吸與危重監護雜志》

辛伐他汀對野百合堿誘導肺動脈高壓大鼠血紅素加氧酶1 表達的影響

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