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Abstract

Pressure overload in the left ventricle of the heart follows a chronic and progressive course, resulting in eventual left heart failure and pulmonary hypertension (PH). The purpose of this research was to determine whether a differential pulmonary gene change of endothelin (ET)-1 and endothelial nitric oxide synthase (eNOS) occurred in adult rats with left ventricular overload. Eight groups of eight rats each were used (four rats with banding and four rats with sham operations). The rats underwent ascending aortic banding for 1 day, 2 weeks, 4 weeks, and 12 weeks before sacrifice. Significant medial hypertrophy of the pulmonary arterioles developed in two groups (4 and 12 weeks). Increased pulmonary arterial pressures were noted in three groups (1 day, 4 weeks, and 12 weeks). The aortic banding led to significant increases in pulmonary preproET-1 messenger RNA (mRNA) at 1 day and 12 weeks, and in pulmonary eNOS mRNA at 1 day and 12 weeks. In addition, there was increased pulmonary eNOS content at 1 day and 12 weeks in the banded rats, and increased lung cGMP levels were observed at 1 day. Increased lung ET-1 levels were also noted at 1 day (banded, 310 ± 12 ng/g protein; sham, 201 ± 12 ng/g protein; P < 0.01), 4 weeks (banded, 232 ± 12 ng/g protein; sham, 201 ± 12 ng/g protein; P < 0.01) and 12 weeks (banded, 242 ± 12 ng/g protein; sham, 202 ± 12 ng/g protein; P < 0.01). This indicates that the upregulated expression of ET-1 developed at least 4 weeks before eNOS expression in the course of PH, and, thus, medication against ET-1 could play a crucial role in treating PH with cardiac dysfunction secondary to aortic banding.

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References

Keck EW. Pulmonary hypertension and pulmonary vascular disease in congenital heart defects. Zeitschrift Fur Kardiolgie 78:65–73, 1989.

Yamaki S, Endo M, Takahashi T. Different grades of medial hypertrophy and intimal changes in small pulmonary arteries among various types of congenital heart disease with pulmonary hypertension. Tohuku J Exp Med 182:83–91, 1997.

Heath D, Edwards JE. The pathology of hypertensive pulmonary vascular disease; a description of six grades of structural changes in the pulmonary arteries with special reference to congenital cardiac septal defects. Circulation 18:533–547, 1958.

Uematsu M, Ohara Y, Navas JP, Nishida K, Murphy TJ, Alexander RW, Nerem RM, Harrison DG. Regulation of endothelial cell nitric oxide synthase mRNA expression by shear stress. Am J Physiol 269: C1371–C1378, 1995.

Palmer RM, Ashton DS, Moncada S. Vascular endothelial cells synthesize nitric oxide from L-arginine. Nature 333:664–666, 1988.

Gibbons GH, Dzau VJ. The emerging concept of vascular remodeling. N Eng J Med 330:1431–1438, 1993.

Miyazaki H, Kondoh M, Watanabe H, Yanagisawa M, Masaki T, Murakami K. Two different forms of endothelin receptors in rat lung. FEBS Lett 257:208–210, 1989.

Le Cras TD, Tyler RC, Xue C, Rengasamy A, Johns RA. Chronic hypoxia upregulates endothelial and inducible nitric oxide synthase gene and protein expression in rat lung. Am J Physiol 270:L164–L170, 1996.

Xue C, Johns RA. Upregulation of nitric oxide synthase correlates temporally with onset of pulmonary vascular remodelling in the hypoxia. Hypertension 28:743–753, 1996.

10.

Li H, Chen SJ, Chen YF, Meng QC, Durand J, Suzanne O, Elton TS. Enhanced endothelin-1 and endothelin receptor gene expression in chronic hypoxia. J Appl Physiol 77:1451–1459, 1994.

11.

Xue C, Johns RA. Endothelial nitric oxide synthase in the lungs of patients with pulmonary hypertension. N Engl J Med 333:1642–1644, 1995.

12.

Dai ZK, Tan MS, Chai CY, Yeh JL, Chou SH, Chiu CC, Jeng AY, Chen IJ, Wu JR. Up-regulation of endothelial nitric oxide synthase and endothelin-1 in pulmonary hypertension secondary to heart failure in aorta-banded rats. Pediatr Pulmonol 37:249–256, 2004.

13.

Pfeifer M, Bruckschlegel G, Holmer SR, Paul M, Reigger AJG, Schunker H. Reciprocal regulation of pulmonary and cardiac angiotensin-converting enzyme in rats with severe left ventricular hypertrophy. Cardiovasc Res 38:125–132, 1998.

14.

Chomczynski P, Sacchi N. Single-step method of RNA isolation by acid guanidinium thiocyanate-phenol-chloroform extraction. Anal Biochem 162:156–159, 1987.

15.

Moraes DL, Colucci WS, Givertz MM. Secondary pulmonary hypertension in chronic heart failure. The role of the endothelium in pathophysiology and management. Circulation 102:1718–1723, 2000.

16.

Itani MM, Talerico MG, Pino PA, Burke-Wolin T. Early regulatory changes in rat pulmonary artery of renin-dependent systemic hypertension models. Am J Respir Cell Mol Biol 15:467–472, 1996.

17.

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 rats. Clin Sci 103:289S–293S, 2002.

18.

Giaid A, Yanagisawa M, Langleben D, Michel RP, Levy R, Shennib H, Kimura S, Masaki T, Duguid WP, Stewart DJ. Expression of endothelin-1 in the lungs of patients with pulmonary hypertension. N Engl J Med 328:1732–1739, 1993.

19.

Driss AB, Devaux C, Henrion D, Duriez M, Thuillez C, Levy BI, Michel JB. Hemodynamic stresses induce endothelial dysfunction and remodeling of pulmonary artery in experimental compensated heart failure. Circulation 101:2764–2770, 2000.

20.

Sakai ET, Miyauchi T, Sakura T, Yamagauchi I, Kobayashi M, Goto K, Sugishita Y. Pulmonary hypertension caused by congestive heart failure is ameliorated by long term application of an endothelin receptor antagonist. J Am Coll Cardiol 28:1580–1588, 1996.

21.

Prie S, Stewart DJ, Dupuis J. Endothelin A receptor blockade improves nitric oxide-mediated vasodilatation in monocrotaline-induced pulmonary hypertension. Circulation 97:2169–2174, 1998.

22.

Bouloumie A, Bauersachs J, Linz W, Scholkens BA, Wiemer G, Fleming I, Busse R. Endothelial dysfunction coincides with an enhanced nitric oxide synthase expression and superoxide anion production. Hypertension 30:934–941, 1997.

23.

Yamashita T, Kawashima S, Ohashi Y, Ozaki M, Rikitake Y, Inoue N, Hirata K, Akita H, Yokoyama M. Mechanisms of reduced nitric oxide/cGMP-mediated vasorelaxation in transgenic mice overexpressing endothelial nitric oxide synthase. Hypertension 36:97–102, 2000.

Differential Change in Expression of Pulmonary ET-1 and eNOS in Rats After Chronic Left Ventricular Pressure Overload

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