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

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.