Browse > Article
http://dx.doi.org/10.4070/kcj.2011.41.2.83

Gene Expressions of Nitric Oxide Synthase and Matrix Metalloproteinase-2 in Monocrotaline-Induced Pulmonary Hypertension in Rats After Bosentan Treatment  

Koo, Hee-Sun (Department of Pediatrics, School of Medicine, Ewha Womans University)
Kim, Kwan-Chang (Department of Thoracic and Cardiovascular Surgery, School of Medicine, Ewha Womans University)
Hong, Young-Mi (Department of Pediatrics, School of Medicine, Ewha Womans University)
Publication Information
Korean Circulation Journal / v.41, no.2, 2011 , pp. 83-90 More about this Journal
Abstract
Background and Objectives: Nitric oxide (NO) is a major endothelium dependent vasomediator and growth inhibitor. NO synthesis is catalyzed by endothelial nitric oxide synthase (eNOS), and NO can also produce peroxynitrite, which activates matrix metalloproteinases (MMPs). The purpose of this study was to determine the gene expression of eNOS and MMP-2 in the lungs of a rat model of pulmonary hypertension after bosentan treatment. Materials and Methods: Six-week-old male Sprague-Dawley rats were treated as follows: control group, subcutaneous (sc) injection of saline; monocrotaline (MCT) group, sc injection of MCT (60 mg/kg); and bosentan group, sc injection of MCT (60 mg/kg) plus 20 mg/day bosentan orally. The rats were sacrificed after 1, 5, 7, 14 and 28 days. Results: The right ventricle/(left ventricle+septum) ratio significantly increased in the MCT group compared to the control group on day 14 and 28. The expression of eNOS messenger ribonucleic acid was significantly increased in the MCT group compared to the control group on day 28. MMP-2 gene expression was significantly increased in the MCT-treated rats compared to the control group on day 5 and 28. Following bosentan treatment to reduce pulmonary hypertension, the expression levels of MMP-2 gene were significantly decreased on day 7 and 28. eNOS and tissue inhibitor of MMPs genes were also significantly decreased on day 28 after bosentan treatment. Conclusion: These results suggest that elevated eNOS expression may be responsible for MMP-2 activation. The causal relationship between eNOS and MMP-2 and their role in pulmonary hypertension require further investigations.
Keywords
Pulmonary hypertension; Monocrotaline; Gene expression; Nitric oxide synthase; Matrix metalloproteinases;
Citations & Related Records
Times Cited By KSCI : 3  (Citation Analysis)
Times Cited By SCOPUS : 7
연도 인용수 순위
1 Murata T, Sato K, Hori M, Ozaki H, Karaki H. Decreased endothelial nitric-oxide synthase (eNOS) activity resulting from abnormal interaction between eNOS and its regulatory proteins in hypoxia-induced pulmonary hypertension. J Biol Chem 2002;277:44085-92.   DOI
2 Everett AD, Le Cras TD, Xue C, Johns RA. eNOS expression is not altered in pulmonary vascular remodeling due to increased pulmonary blood flow. Am J Physiol 1998;274:L1058-65.
3 Channick RN, Simonneau G, Sitbon O, et al. Effects of the dual endothelin-receptor antagonist bosentan in patients with pulmonary hypertension: a randomised placebo-controlled study. Lancet 2001;358: 1119-23.   DOI   ScienceOn
4 Clozel M, Hess P, Rey M, Iglarz M, Binkert C, Qiu C. Bosentan, sildenafil, and their combination in the monocrotaline model of pulmonary hypertension in rats. Exp Biol Med 2006;231:967-73.
5 Frisdal E, Gest V, Vieillard-Baron A, et al. Gelatinase expression in pul-monary arteries during experimental pulmonary hypertension. Eur Respir J 2001;18:838-45.   DOI   ScienceOn
6 Lepetit H, Eddahibi S, Fadel E, et al. Smooth muscle cell matrix metalloproteinases in idiopathic pulmonary arterial hypertension. Eur Respir J 2005;25:834-42.   DOI   ScienceOn
7 Morrel NW, Adnot S, Archer SL, et al. Cellular and molecular basis of pulmonary arterial hypertension. J Am Coll Cardiol 2009;54(1 Suppl): S20-31.
8 Lim KA, Shim JY, Cho SH, Kim KC, Han JJ, Hong YM. Effect of endothelin receptor blockade on monocrotaline-induced pulmonary hypertension in rats. Korean J Pediatr 2009;52:689-95.   DOI   ScienceOn
9 Miyauchi T, Yorikane R, Sakai S, et al. Contribution of endogenous endothelin-1 to the progression of cardiopulmonary alterations in rats with monocrotaline-induced pulmonary hypertension. Circ Res 1993; 73:887-97.   DOI   ScienceOn
10 Itoh T, Nagaya N, Fujii T, et al. A combination of oral sildenafil and be-raprost ameliorates pulmonary hypertension in rats. Am J Respir Crit Care Med 2004;169:34-8.   DOI
11 Lim KY, Kim KC, Cho MS, Lee BR, Kim HS, Hong YM. Gene expression of endothelin-1 and endothelin receptor A on monocrotaline-induced pulmonary hypertension in rats after bosentan treatment. Korean Cir J 2010;40:459-64.   DOI   ScienceOn
12 Hampl V, Herget J. Role of nitric oxide in the pathogenesis of chronic pulmonary hypertension. Physiol Rev 2000;80:1337-72.
13 Giaid A, Saleh D. Reduced expression of endothelial nitric oxide synthase in the lungs of patients with pulmonary hypertension. N Engl J Med 1995;333:214-21.   DOI   ScienceOn
14 Komai H, Naito Y, Aimi Y, Kimura H. Nitric oxide synthase expression in lungs of pulmonary hypertensive patients with heart disease. Cardiovasc Pathol 2001;10:29-32.   DOI   ScienceOn
15 Kim MY, Kim YK, Jung YW, Kim WT, Kwon TH, Lee DS. The protective effect of simvastatin on monocrotaline-induced pulmonary hypertension in rats. Korean Circ J 2008;38:313-9.   DOI   ScienceOn
16 Resta TC, Gonzales RJ, Dail WG, Sanders TC, Walker BR. Selective upregulation of arterial endothelial nitric oxide synthase in pulmonary hypertension. Am J Physiol 1997;272:H806-13.
17 Hessel MH, Steendijk P, den Adel B, Schutte CI, van der Laarse A. Ch-aracterization of right ventricular function after monocrotaline-induced pulmonary hypertension in the intact rat. Am J Physiol Heart Circ Physiol 2006;291:H2424-30.   DOI
18 Umar S, Hessel M, Steendijk P, et al. Activation of signaling molecules and matrix metalloproteinases in right ventricular myocardium of rats with pulmonary hypertension. Pathol Res Pract 2007;203:863-72.   DOI   ScienceOn
19 Tyler RC, Muramatsu M, Abman SH, et al. Variable expression of endothelial NO synthase in three forms of rat pulmonary hypertension. Am J Physiol 1999;276:L297-303.
20 Mathew R, Yuan N, Rosenfeld L, Gewitz MH, Kumar A. Effects of mo-nocrotaline on endothelial nitric oxide synthase expression and sulfhydryl levels in rat lungs. Heart Dis 2002;4:152-8.   DOI   ScienceOn
21 Chou TF, Wu MS, Chien CT, Yu CC, Chen CF. Enhanced expression of nitric oxide synthase in the early stage after increased pulmonary blood flow in rats. Eur J Cardiothorac Surg 2002;21:331-6.   DOI   ScienceOn
22 Dai ZK, Tan MS, Chai CY, Chen IJ, Jeng AY, Wu JR. Effects of increased pulmonary flow on the expression of endothelial nitric oxide synthase and endothelin-1 in the rat. Clin Sci 2002;103(Suppl 48): 289S-93S.   DOI
23 Black SM, Fineman JR, Steinhorn RH, Bristow J, Soifer SJ. Increased endothelial NOS in lambs with increased pulmonary blood flow and pulmonary hypertension. Am J Physiol 1998;275:H1643-51.
24 Xue C, Johns RA. Upregulation of nitric oxide synthase correlates temporally with onset of pulmonary vascular remodeling in the hypoxic rat. Hypertension 1996;28:743-53.   DOI   ScienceOn
25 Fagan KA, Morrissey B, Fouty BW, et al. Upregulation of nitric oxide synthase in mice with severe hypoxia-induced pulmonary hypertension. Respir Res 2001;2:306-13.   DOI   ScienceOn
26 Le Cras TD, Xue C, Rengasamy A, Johns RA. Chronic hypoxia upregulates endothelial and inducible NO synthase gene and protein expression in rat lung. Am J Physiol 1996;270:L164-70.
27 Resta TC, Chicoine LG, Omdahl JL, Walker BR. Maintained upregulation of pulmonary eNOS gene and protein expression during recovery from chronic hypoxia. Am J Physiol 1999;276:H699-708.
28 Le Cras TD, McMurtry IF. Nitric oxide production in the hypoxic lung. Am J Physiol Lung Cell Mol Physiol 2001;280:L575-82.   DOI
29 Mukhopadhyay S, Xu F, Sehgal PB. Aberrant cytoplasmic sequestration of eNOS in endothelial cells after monocrotaline, hypoxia, and senescence: live-cell caveolar and cytoplasmic NO imaging. Am J Phy-siol Heart Circ Physiol 2007;292:H1373-89.   DOI
30 Wang QD, Li XS, Pernow J. The nonpeptide endothelin receptor antagonist bosentan enhances myocardial recovery and endothelial function during reperfusion of the ischemic rat heart. J Cardiovasc Pharmacol 1995;26(Suppl 3):S445-7.   DOI
31 Winkler MK, Foldes JK, Bunn RC, Fowlkes JL. Implications for matrix metalloproteinases as modulators of pediatric lung disease. Am J Physiol Lung Cell Mol Physiol 2003;284:L557-65.   DOI