Simvastation Induces Heme Oxygenase-1 Expression in Monocrotaline-Induced Pulmonary Hypertension Rats_Chinese Journal of Respiratory and Critical Care Medicine

Authors：

ZHANG Weihua ¹ , LU Weixuan ² , ZHANG Yunjian ³ , YU Bingxiang. ¹

Department of Internal Medical Center, General Hospital of PLA. Beijing, 100853, ChinaCorresponding Author: ZHANGWei-hua, E-mail: whuazhang@ 126. com;

Corresponding author：

Keywords：

Simvastatin; Pulmonary hypertension; Heme oxygenase-1; Monocrotaline

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Objective To investigate the effects of simvastatin on monocrotaline-induced pulmonary hypertension in rats, and explore the potential mechanism of simvastatin by blocking heme oxygenase-1( HO-1) expression. Methods 52 male Sprague-Dawley rats were randomly divided into five groups, ie. a control group, a simvastatin control group, a pulmonary hypertension model group, a simvastatin treatment group, a ZnPP ( chemical inhibitor of HO) group. Mean pulmonary arterial pressure ( mPAP) and right ventricular systolic pressure ( RVSP) were detected by right heart catheter at 5th week. Right ventricular hypertrophy index ( RVHI) was calculated as the right ventricle to the left ventricle plus septum weight. Histopathology changes of small intrapulmonary arteries were evaluated via image analysis system.
Immunohistochemical analysis was used to investigate the expression and location of HO-1. HO-1 protein level in lung tissue were determined by western blot. Results Compared with the model group, simvastatin treatment decreased mPAP and RVHI significantly [ ( 35. 63 ±5. 10) mm Hg vs. ( 65. 78 ±15. 51) mm Hg,
0. 33 ±0. 05 vs. 0. 53 ±0. 06, both P lt; 0. 05 ] . Moreover, simvastatin treatment partially reversed the increase of arterial wall area and arterial wall diameter [ ( 50. 78 ±9. 03 ) % vs. ( 65. 92 ±7. 19) % ,( 43. 75 ±4. 23) % vs. ( 52. 00 ±5. 35) % , both P lt; 0. 01) . In the model group, HO-1 staining was primarily detected in alveolar macrophages. Simvastatin treatment increased HO-1 protein expression significantly, especially in the thickened smooth muscle layer and alveolar macrophages. Inhibiting HO-1 expression using ZnPP resulted in a loss of the effects of simvastatin. mPAP in the ZnPP group was ( 52. 88±17. 45) mm Hg, while arterial wall area and arterial wall diameter were ( 50. 78 ±9. 03) % and ( 52. 00 ±5. 35) % , respectively. Conclusions Simvastatin attenuates established pulmonary arterial hypertension and
pulmonary artery remodeling in monocrotaline-induced pulmonary hypertension rats. The effect of simvastatin is associated with HO-1.

Citation： ZHANG Weihua,LU Weixuan,ZHANG Yunjian,YU Bingxiang.. Simvastation Induces Heme Oxygenase-1 Expression in Monocrotaline-Induced Pulmonary Hypertension Rats. Chinese Journal of Respiratory and Critical Care Medicine, 2010, 9(5): 523-527. doi: Copy

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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.
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10.	Lalich JJ, Merkow L. Pulmonary arteries produced in rats by feeding crotolaria spectabilis. Lab Invest, 1961, 10 : 744-750.
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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.

Chinese Journal of Respiratory and Critical Care Medicine

Simvastation Induces Heme Oxygenase-1 Expression in Monocrotaline-Induced Pulmonary Hypertension Rats

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