瑞舒伐他汀对野百合碱诱导大鼠肺动脉高压的干预及机制研究

Intervention of rosuvastatin in monocrotaline-induced pulmonary artery hypertension in rats and its mechanism

目的探讨瑞舒伐他汀干预野百合碱诱导大鼠肺动脉高压的作用及可能机制。方法 48只雄性SD大鼠随机分为正常对照组(n=8)和野百合碱组(n=40),正常对照组予皮下注射生理盐水,野百合碱组一次性皮下注射1%野百合碱50mg/kg,4周后再随机分为肺动脉高压组(n=16)、瑞舒伐他汀低剂量组[2mg/(kg·d),n=12]、瑞舒伐他汀高剂量组[10mg/(kg·d),n=12],瑞舒伐他汀低剂量组和高剂量组于野百合碱注射第4周末起每日给予瑞舒伐他汀灌胃,正常对照组、肺动脉高压组仅予生理盐水灌胃,干预4周。观察各组大鼠的一般情况,各组干预结束后测量平均右心室压力(mRVP)、平均肺动脉压力(mPAP)和右心室肥厚指数(RVHI);HE染色观察肺小动脉管壁厚度与血管外径之比(WT%)和管壁面积占血管总面积的百分比(WA%);Western blot法检测骨形成蛋白Ⅱ型受体(BMPR-Ⅱ)、Smad4蛋白在肺动脉中的表达水平。结果瑞舒伐他汀能降低mRVP[瑞舒伐他汀低剂量组(24.58±1.38)、瑞舒伐他汀高剂量组(21.56±3.05)比肺动脉高压组(35.28±2.81)mmHg,均P<0.05],降低mPAP[瑞舒伐他汀低剂量组(30.26±1.57)、瑞舒伐他汀高剂量组(27.88±2.17)比肺动脉高压组(41.23±2.63)mmHg,均P<0.05],减轻肺小动脉管壁厚度(P<0.01)、右心室肥厚程度(均P<0.05),上调肺动脉BMPR-Ⅱ和Smad4蛋白的表达(均P<0.05)。结论瑞舒伐他汀缓解已经形成的肺动脉高压,减轻右心室肥厚,可能是通过上调BMPR-Ⅱ、Smad4蛋白的表达来实现的。

Objective To investigate the effects of rosuvastatin on monocrotaline-induced pulmonary arterial hyper- tension in rats and its mechanisms. Methods A total of forty eight male Sprague-Dawley rats were randomly divid- ed into normal control group （n= 8） and monocrotaline group （n = 40）. Rats in control group received saline by subcutaneous injection, and the rats in monocrotaline group received single injection of monocrotaline （MCT, 50 mg/kg） subcutaneously. Four weeks later, the rats in monocrotaline group were randomized into three sub- groups： pulmonary arterial hypertension group （M group, n = 16 ）, low-dose rosuvastatin treatment group [2 mg/（kg . d）, R2 group, n=12）, and high-dose rosuvastatin treatment group [10 mg/（kg . d）, R10 group, n= 12]. R2 group and R10 group were treated with rosuvastatin by daily gavage at the fourth weekend of monocrotal- ine injection, while control group and M group only received saline by gavage. After four weeks of these interven- tions, mean right ventricular pressure （mRVP）, mean pulmonary artery pressure （mPAP）, and right ventrieular hy- pertrophy index [RV/（LV±S）] were measured. The percentage wall thickness [WT%, defined as （medial thick- ness× 2/external diameter） × 100] and percentage wall area [WA%, defined as （ wall area/total area） ×100] of pul- monary arteriole were determined by hematoxylin and eosin （HE） staining. The protein expression levels of bone morphogenetic protein Ⅱ receptor （BMPR-Ⅱ） and Smad4 in pulmonary artery were detected by Western blot. Results In R2 group and R10 group, rosuvastatin significantly decreased mRVP [（24.58±1.38） and （21.56± 3.05） vs M group （35.28±2.81） mm Hg, all P〈0.05], mPAP [（30.26±1.57） and （27.88±2.17） vs M group （41.23±2. 631 mm Hg, all P〈0. 05]. Pulmonary arteriole wall thickness （P〈0.01） and right ventricular hypertrophy（all P〈0. 05） were also reduced. While the expression of BMPR-Ⅱ and Smad4 protein in pulmonary artery were increased as compared with M group （all P〈0.05）. Conclusion Rosuvastatin ameliorates pulmonary artery hy- pertension and alleviates right ventricular hypertrophy possibly by up-regulating the protein expression of BMPR-Ⅱ and Smad4 in pulmonary artery.