Korean Circ J.  2008 Jun;38(6):313-319. 10.4070/kcj.2008.38.6.313.

The Protective Effect of Simvastatin on Monocrotaline-Induced Pulmonary Hypertension in Rats

• Kim MY
• Kim YK
• Jung YW
• Kim WT
• Kwon TH
• Lee DS

• KMID: 2225778
• DOI: http://doi.org/10.4070/kcj.2008.38.6.313

Abstract

BACKGROUND AND OBJECTIVES: Pulmonary hypertension is characterized by abnormal proliferation of vascular endothelial cells and smooth muscle cells, and progressive pulmonary microvascular leakage that leads to pulmonary edema. This study was designed to investigate the protective effect of simvastatin on monocrotaline (MCT)-induced pulmonary hypertension and the role of the aquaporin (AQP) water channels.
MATERIALS AND METHODS
Twenty one 8-week-old rats were randomized to the control, MCT (60 mg/kg, sc) and the MCT plus simvastatin (5 mg/kg/day, po) groups. Four weeks later, the systolic right ventricular pressure, the right ventricular hypertrophy, the medial wall thickness of the peribronchiolar artery and pulmonary arterioles and the renal function were measured to examine the effects of MCT and simvastatin in the rats. Western blotting for lung aquaporin1 (AQP1) and renal aquaporin2 (AQP2) was performed to analyze the effects of MCT and simvastatin on the AQP water channels.
RESULTS
Treatment with simvastatin reduced the MCT-induced enhanced right ventricular pressure (32.3+/-2.1 vs. 52.4+/-3.9 mmHg, respectively; p<0.05), the right ventricular hypertrophy (0.32+/-0.03 vs. 0.48+/-0.07, respectively; p<0.05) and the increased medial wall thickness of the peribronchiolar artery (0.14+/-0.02 vs. 0.28+/-0.02, respectively; p<0.05) and pulmonary arterioles (0.15+/-0.04 vs. 0.29+/-0.11, respectively; p<0.05). The decreased expression of lung AQP1 and renal AQP2 protein after MCT treatment was normalized by simvastatin treatment (p<0.05). Additionally, simvastatin treatment significantly reduced the perivascular and interstitial edema in the rats' lungs without major alterations of renal function.
CONCLUSION
These results suggest that simvastatin attenuates the MCT-induced pulmonary hypertension and the pulmonary edema by up-regulation of lung AQP1. Modulation of AQP may be one of the important mechanism of simvastatin.

Keyword

Pulmonary circulation; Pulmonary hypertension; Statins

MeSH Terms

Animals
Aquaporin 2
Arteries
Arterioles
Blotting, Western
Edema
Endothelial Cells
Hypertension, Pulmonary
Hypertrophy, Right Ventricular
Lung
Monocrotaline
Myocytes, Smooth Muscle
Pulmonary Circulation
Pulmonary Edema
Rats
Simvastatin
Up-Regulation
Ventricular Pressure
Aquaporin 2
Monocrotaline
Simvastatin

Figure

• 

  Fig. 1 The systolic right ventricle pressure. Simvaststin (S) prevented the development of pulmonary arterial hypertension in the monocrotaline (MCT) treated rats. However, simvastatin treatment did not suppress the right ventricular pressure to normal values. The results are expressed as means±SDs. *p<0.05 vs. control, †p<0.05 vs. MCT.

• 

  Fig. 2 The ratio of the right ventricle (RV) to left ventricle (LV) plus septum weight. The monocrotaline (MCT)-induced RV hypertrophy was attenuated after simvastatin (S) treatment. However, simvastatin treatment did not completely suppress the RV hypertrophy to normal values. Values are expressed as means±SDs. *p<0.05 vs. control, †p<0.05 vs. MCT.

• 

  Fig. 3 Light microscopic findings of lung. Representative photographs of the peribronchiolar muscular pulmonary artery (A-C, ×200), the pulmonary arteriole (D-F, ×400), and the histological change of the lung (G-I, ×200). The increased medial wall thickness in the monocrotaline (MCT) treatment group was reduced with simvastatin (S) treatment. MCT induced severe perivascular and interstitial edema, but simvastatin treatment markedly reduced the pulmonary edema. Hematoxylin and eosin staining. Bar=50 µm. Br: bronchiole.

• 

  Fig. 4 AQP1 in lung. The expression of lung AQP1 was significantly diminished in the monocrotaline (MCT)-induced pulmonary hypertension rats. But the lung AQP1 protein expression was normalized by simvastatin (S) treatment. Values are expressed as means±SDs. *p<0.05 vs. control, †p<0.05 vs. MCT. AQP: aquaporin.

• 

  Fig. 5 AQP2 in kidney. The expression of renal AQP2 was significantly diminished in the monocrotaline (MCT)-induced pulmonary hypertension rats. But the renal AQP2 protein expression was normalized by simvastatin (S) treatment. Values are expressed as means±SDs. *p<0.05 vs. control, †p<0.05 vs. MCT. AQP: aquaporin.

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