Department of Pharmacology, School of Pharmacy, Ningxia Medical University, PR China.
Eur J Pharmacol. 2011 Sep;666(1-3):165-72. doi: 10.1016/j.ejphar.2011.05.035. Epub 2011 May 30.
This study was designed to investigate whether rosuvastatin could attenuate monocrotaline-induced pulmonary hypertension via regulation of Akt/eNOS signaling pathway and asymmetric dimethylarginine (ADMA) metabolism in rats. After a single-dose injection of monocrotaline (60 mg/kg), oral administration of rosuvastatin (5mg/kg) was started from day 1 to day 28 (preventive administration) or from day 15 to day 28 (therapeutic administration), or with vehicle as corresponding controls. 28 days after monocrotaline, significant pulmonary hypertension characterized by pulmonary arterial medial wall thickening, right ventricular hypertrophy and right heart failure was observed. Rosuvastatin (5mg/kg, for 14 days and 28 days) treatment significantly attenuated monocrotaline-induced pulmonary vascular remodeling, right ventricular hypertrophy and dysfunction, and normalized the down-regulated pulmonary Akt/p-Akt and eNOS/p-eNOS expressions, while increased DDAH2 expression accompanied by decreased serum level of ADMA. However expression of PRMT1 and GSK3β/p-GSK3β did not differ among all groups (all P>0.05). We concluded that rosuvastatin inhibits monocrotaline-induced pulmonary hypertension through normalization of Akt, eNOS and DDAH2 expressions, and decreasing the level of ADMA.
本研究旨在探讨瑞舒伐他汀能否通过调节 Akt/eNOS 信号通路和不对称二甲基精氨酸（ADMA）代谢来减轻野百合碱诱导的大鼠肺动脉高压。单次注射野百合碱（60mg/kg）后，从第 1 天到第 28 天（预防给药）或从第 15 天到第 28 天（治疗给药）开始给予瑞舒伐他汀（5mg/kg）口服治疗，或给予相应的载体对照。野百合碱后 28 天，观察到肺动脉中层壁增厚、右心室肥厚和右心衰竭等显著的肺动脉高压特征。瑞舒伐他汀（5mg/kg，14 天和 28 天）治疗显著减轻了野百合碱诱导的肺血管重构、右心室肥厚和功能障碍，并使下调的肺 Akt/p-Akt 和 eNOS/p-eNOS 表达正常化，同时增加了 DDAH2 表达，伴随血清 ADMA 水平降低。然而，PRMT1 和 GSK3β/p-GSK3β 的表达在所有组之间没有差异（均 P>0.05）。我们得出结论，瑞舒伐他汀通过使 Akt、eNOS 和 DDAH2 的表达正常化并降低 ADMA 的水平来抑制野百合碱诱导的肺动脉高压。
