Korean Circ J.  2011 Sep;41(9):518-527. 10.4070/kcj.2011.41.9.518.

Changes of Pulmonary Pathology and Gene Expressions After Simvastatin Treatment in the Monocrotaline-Induced Pulmonary Hypertension Rat Model

• Lee YH
• Kim KC
• Cho MS
• Hong YM

• KMID: 2094104
• DOI: http://doi.org/10.4070/kcj.2011.41.9.518

Abstract

BACKGROUND AND OBJECTIVES
Simvastatin's properties are suggestive of a potential pathophysiologic role in pulmonary hypertension. The objectives of this study were to investigate changes of pulmonary pathology and gene expressions, including endothelin (ET)-1, endothelin receptor A (ERA), inducible nitric oxide synthase (NOS2), endothelial nitric oxide synthase (NOS3), matrix metalloproteinase (MMP) 2, tissue inhibitor of matrix metalloproteinases (TIMP) and caspase 3, and to evaluate the effect of simvastatin on monocrotaline (M)-induced pulmonary hypertension.
MATERIALS AND METHODS
Six week old male Sprague-Dawley rats were treated, as follows: control group, subcutaneous (sc) injection of saline; M group, sc injection of M (60 mg/kg); and simvastatin group, sc injection of M (60 mg/kg) plus 10 mg/kg/day simvastatin orally.
RESULTS
On day 28, right ventricular hypertrophy (RVH) significantly decreased in the simvastatin group compared to the M group. Similarly, right ventricular pressure significantly decreased in the simvastatin group on day 28. From day 7, the ratio of medial thickening of the pulmonary artery was significantly increased in the M group, but there was no significant change in the simvastatin group. The number of muscular pulmonary arterioles was significantly reduced in the simvastatin group. On day 5, gene expressions of ET-1, ERA, NOS2, NOS3, MMP and TIMP significantly decreased in the simvastatin group.
CONCLUSION
Administration of simvastatin exerted weak inhibitory effects on RVH and on the number of muscular pulmonary arterioles, during the development of M-induced pulmonary hypertension in rats. Simvastatin decreased gene expressions on day 5.

Keyword

Hypertension, pulmonary; Gene expression; Monocrotaline; Simvastatin

MeSH Terms

Animals
Arterioles
Caspase 3
Endothelins
Gene Expression
Humans
Hypertension, Pulmonary
Hypertrophy, Right Ventricular
Male
Matrix Metalloproteinases
Monocrotaline
Nitric Oxide Synthase Type II
Nitric Oxide Synthase Type III
Pulmonary Artery
Rats
Rats, Sprague-Dawley
Receptors, Endothelin
Simvastatin
Ventricular Pressure
Caspase 3
Endothelins
Matrix Metalloproteinases
Monocrotaline
Nitric Oxide Synthase Type II
Nitric Oxide Synthase Type III
Receptors, Endothelin
Simvastatin

Figure

• 

  Fig. 1 Typical example of RT-PCR products are shown for the level of ET-1, ERA, NOS2, NOS3, MMP 2 and TIMP mRNA measured in the lung tissue. The RT-PCR products from the transcripts of ET-1, ERA, NOS2, NOS3, MMP2, TIMP, Casp 3 and GAPDH were 156 bp, 118 bp, 107 bp, 140 bp, 137 bp, 133 bp 100 and 89 bp, respectively. ET-1: endothelin-1, ERA: endothelin receptor A, NOS 2: inducible nitric oxide synthase, NOS 3: endothelial nitric oxide synthase, MMP-2: matrix metalloproteinase 2, TIMP: tissue inhibitor of matrix metalloproteinases, Casp3: caspase 3, GAPDH: glyceraldehyde 3-phosphate dehydrogenase.

• 

  Fig. 2 Photographs of pulmonary arterioles in the three investigated groups (Victoria blue stain ×400). A: the muscular layer of pulmonary arterioles was normal in C group. B: the medial layer of pulmonary arterioles was progressively thickened after M injection in M group. C: the medial wall thickness after M injection was significantly attenuated in the simvastatin group. C: control group, M: monocrotaline group, S: simvastatin group.

• 

  Fig. 3 Gene expressions of endothelin-1 in the lungs, determined at day 1, day 5, 1 week, 2 weeks and 4 weeks after simvastatin treatment. *p<0.05 vs. the corresponding value in the C group, †p<0.05 vs. the corresponding value in the M group. C: control, M: monocrotaline, S: simvastatin.

• 

  Fig. 4 Gene expressions of endothelin receptor A in the lungs, determined at day 1, day 5, 1 week, 2 weeks and 4 weeks after simvastatin treatment. *p<0.05 vs. the corresponding value in the C group, †p<0.05 vs. the corresponding value in the M group. C: control, M: monocrotaline, S: simvastatin.

• 

  Fig. 5 Gene expressions of inducible nitric oxide synthase in the lungs, determined at day 1, day 5, 1 week, 2 weeks and 4 weeks after simvastatin treatment. *p<0.05 vs. the corresponding value in the C group, †p<0.05 vs. the corresponding value in the M group. C: control, M: monocrotaline, S: simvastatin.

• 

  Fig. 6 Gene expressions of endothelial nitric oxide synthase mRNA in the lungs, determined at day 1, day 5, 1 week, 2 weeks and 4 weeks after simvastatin treatment. *p<0.05 vs. the corresponding value in the C group, †p<0.05 vs. the corresponding value in the M group. C: control, M: monocrotaline, S: simvastatin.

• 

  Fig. 7 Gene expressions of matrix metalloproteinase 2 in the lungs, determined at day 1, day 5, 1 week, 2 weeks and 4 weeks after simvastatin treatment. *p<0.05 vs. the corresponding value in the C group, †p<0.05 vs. the corresponding value in the M group. C: control, M: monocrotaline, S: simvastatin.

• 

  Fig. 8 Gene expressions of tissue inhibitor of matrix metalloproteinases in the lungs, determined at day 1, day 5, 1 week, 2 weeks and 4 weeks after simvastatin treatment. *p<0.05 vs. the corresponding value in the C group, †p<0.05 vs. the corresponding value in the M group. C: control, M: monocrotaline, S: simvastatin.

• 

  Fig. 9 Gene expressions of caspase 3 in the lungs, determined at day 1, day 5, 1 week, 2 weeks and 4 weeks after simvastatin treatment. †p<0.05 vs. the corresponding value in the M group. C: control, M: monocrotaline, S: simvastatin.

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