| ObjectiveTo investigate the preventive and therapeutic effects of rosuvastatin on monocrotaline-induced pulmonary arterial hypertension in rats.MethodsRats received a single subcutaneous injection of monocrotaline (MCT, 50 mg/kg), to induces pulmonary arterial hypertension. Normal control rats were just injected with saline. Rats received prevention and treatmen with rosuvastatin before and after development of pulmonary arterial hypertension. In the prevention protocol:32 male Sprague-Dawley rats were randomly divided into four groups: pulmonary arterial hypertension group(MCT4W), low-dose rosuvastatin prevention group(2mg/kg/d, Ros2p), high-dose rosuvastatin prevention group(10mg/kg/d, Ros10p), normal control group(Ctr4W). From the day MCT injection on, rats were prevented with rosuvastatin by daily gavage for 4 weeks. Normal control group and pulmonary arterial hypertension group just received vehicle by gavage. In the treatment protocol: 52 male Sprague-Dawley rats were randomly divided into four groups: pulmonary arterial hypertension group(MCT8W,n=20), low-dose rosuvastatin treatment group (2mg/kg/d,Ros2t,n=12), high-dose rosuvastatin treatment group(10mg/kg/d,Ros10t, n=12), normal control group(Ctr8W,n=8). Four weeks after MCT injection, rats were treated with rosuvastatin by daily gavage for 4 weeks. Normal control group and pulmonary arterial hypertension group just received vehicle by gavage. Rats'general state or death were observed through the whole process. At the end of process, right ventricular systolic pressure(RVSP) and mean pulmonary arterial pressure(mPAP) were measured by cannulation through the right jugular vein. Right ventricular hypertrophy and wall thickness of small pulmonary artery were analysed. The levels of PCNA and eNOS protein expression in pulmonary artery were assessed by immunohistochemistry. RT-PCR was used to assess Changes of Rock-1 and eNOS mRNA expression in lung tissue.Results1 Survival analysis: At 4th weekend, all rats in the prevention protocol survived. At 8th weekend, survival rates of group MCT8W,Ros2t and Ros10t were 30%, 58.3% and 75% in the treatment protocol. Compared with MCT8W, the log-rank test's P values of Ros2t , Ros10t were both small than 0.05.2 Hemodynamics,pulmonary vascular morphology and right ventricular hyper- trophy assessment: In the prevention protocol, compared with normal control group, MCT4W rats exhibited higher RVSP and mPAP(P<0.01), increased wall thickness of small pulmonary artery(P<0.01) and more right ventricular hypertrophy(P<0.01). Compared with group MCT4W, rosuvastatin prevention groups exhibited lower RVSP and mPAP(P<0.01), decreased wall thickness of small pulmonary artery(P<0.01) and less right ventricular hypertrophy(P<0.01), and have statistical difference between doses(P<0.05), but have statistical difference compared with normal control group(P<0.01). In the treatment protocol, compared with normal control group, MCT8W rats exhibited higher RVSP and mPAP(P<0.01), increased wall thickness of small pulmonary artery(P<0.01) and more right ventricular hypertrophy(P<0.01). Compared with group MCT8W, rosuvastatin treatment groups exhibited lower RVSP and mPAP(P<0.01), decreased wall thickness of small pulmonary artery(P<0.01) and less right ventricular hypertrophy(P<0.01), and have statistical difference between doses(P<0.05), but have statistical difference compared with normal control group(P<0.01).3 PCNA expression of SMC and eNOS expression of EC in small pulmonary Artery: Compared with normal control group respectively, PCNA expressions of SMC in MCT4W and MCT8W group were significantly higher(P<0.01). After prevented or treated with rosuvastatin, PCNA expressions were significantly inhibited(P<0.01). Compared with normal control group respectively, eNOS expressions of EC in MCT4W and MCT8W group were significantly lower(P<0.01). After prevented or treated with rosuvastatin, eNOS expression were significantly restored(P<0.01).4 Rock-1 and eNOS mRNA expressions of lung tissue: Compared with normal control group respectively, Rock-1 mRNA expressions of lung tissue significantly increased in MCT4W and MCT8W group(P<0.01). After prevented or treated with rosuvastatin, Rock-1 mRNA expressions significantly were inhibited(P<0.05). Compared with normal control group respectively, eNOS mRNA expressions of lung tissue significantly decreased in MCT4W and MCT8W group(P<0.01). After prevented or treated with rosuvastatin, eNOS mRNA expressions significantly were restored(P<0.05).Conclusions1 MCT induced pulmonary artery hypertension and right ventricular hypertrophy with a subsequent high mortality rate in rats. Rosuvastatin lowered pulmonary artery hypertension, decreased right ventricular hypertrophy and improved survival in a dose-dependent manner partly.2 The mechanisms of preventive and therapeutic effects of rosuvastatin on monocrotaline-induced pulmonary arterial hypertension may be inhibition of Rock-1 expression, inhibition of smooth muscle cell proliferation and restoration of endothelial cell functions. |
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