瑞舒伐他汀干预野百合碱诱导大鼠肺动脉高压的实验研究

Effects of rosuvastatin on monocrotaline-induced pulmonary artery hypertension in rats

目的探讨他汀类药物改善内皮细胞功能、抗增殖等降脂外作用在防治肺动脉高压中的作用及可能机制。方法雄性sD大鼠，体重（255．7±12．5）g，皮下注射野百合碱诱导大鼠形成肺动脉高压，肺动脉高压形成前后分别接受瑞舒伐他汀预防和治疗。预防实验：32只SD大鼠随机分为4组，分别为瑞舒伐他汀低剂量（2mg·kg～·d^-1）预防组（n=8）、瑞舒伐他汀高剂量（10mg·kg^-1·d。）预防组（n=8）、肺动脉高压4周组（n=8）和正常对照4周组（n=8），野百合碱注射当日起预防组每日予瑞舒伐他汀灌胃至第4周末，正常对照组、肺动脉高压4周组仅予生理盐水灌胃。治疗实验：52只sD大鼠随机分为4组，分别为瑞舒伐他汀低剂量（2mg·kg^-1·d“）治疗组（／7,=12）、瑞舒伐他汀高剂量（10mg·kg^-1·d^-1）治疗组（n=12）、肺动脉高压8周组（／Z=20）和正常对照8周组（n=8），野百合碱注射4周后治疗组每日予瑞舒伐他汀灌胃至第8周末，正常对照组、肺动脉高压8周组仅予生理盐水灌胃。比较各组生存率、平均肺动脉压（mPAP）、肺小动脉管壁厚度、右心室肥厚程度，比较肺小动脉增殖细胞核抗原（PCNA）、内皮型一氧化氮合酶（eNOS）蛋白表达水平，比较肺组织Rho激酶1（ROCK-1）、eNOS mRNA表达水平。结果预防实验大鼠均存活，肺动脉高压形成之后瑞舒伐他汀治疗能改善生存率（瑞舒伐他汀低剂量治疗组、瑞舒伐他汀高剂量治疗组与肺动脉高压8周组比较为58％、75％比30％，P均〈0．05）；肺动脉高压形成之前和之后瑞舒伐他汀预防和治疗均能降低mPAP[预防实验：瑞舒伐他汀低剂量预防组、瑞舒伐他汀高剂量预防组与肺动脉高压4周组比较为（27．53±3．43）mmHg（1mmHg=0．133kPa）、（25．72±1．76）mmHg比（36．054-2．45）mmHg，P均〈0．01；治疗实验：瑞舒伐他汀低剂量治疗组、瑞舒伐他汀高剂量治疗组与肺动脉高压8周组比较为（30．39±3．17）mmHg、（27．59±1．99）mmHg比（40．68±1．39）mmHg，P均〈0．01]，减轻肺小动脉管壁增厚、右心室肥厚程度（P均〈0．01），下调肺小动脉平滑肌细胞PCNA表达（P均〈0．01），上调内皮细胞eNOS表达（P均〈0．05），抑制ROCK-1基因表达（P均〈0．05），有一定的剂量依赖性（P均〈0．05）。结论瑞舒伐他汀防治肺动脉高压可能是通过抑制ROCK-1基因表达，抑制肺动脉平滑肌增殖和恢复内皮细胞功能等机制来实现的。

Objective To investigate the effects of rosuvastatin on monocrotaline （MCT）-induced pulmonary artery hypertension in rats. Methods Pulmonary arterial hypertension was induced by a single subcutaneous injection of monocrotaline （50 mg/kg） in rats. In the prevention protocol, 32 male Sprague- Dawley rats were randomly divided into four groups （ n = 8 each） ： low-dose rosuvastatin prevention group （2 mg · kg^-1 · d^-1 ）, high-dose rosuvastatin prevention group （ 10 mg · kg^-1 · d^-1 ）, pulmonary arterial hypertension group, normal control group. Beginning on the MCT injection day, rats were treated with rosuvastatin by daily gavage for 4 weeks. Normal control group and pulmonary arterial hypertension group received vehicle by gavage. In the treatment protocol, 52 male Sprague-Dawlev rats were randomly dividedinto four groups （n = 13 each）： low-dose rosuvastatin treatment group （2 mg· kg^-1 · d^-1 ）, high-dose rosuvastatin treatment group（ 10 mg · kg^-1 · d^-1 ）, pulmonary arterial hypertension group, normal control group. Four weeks after MCT injection, rats were treated with rosuvastatin by daily gavage for 4 weeks. Normal control group and pulmonary arterial hypertension group received vehicle by gavage. At the end of study, survival rates, mean pulmonary arterial pressure （mPAP）, wall thickness of small pulmonary artery and right ventricular hypertrophy among groups were compared. The expression levels of proliferating cell nuclear antigen （PCNA） and endothelial nitricoxide synthase （eNOS） protein in small pulmonary artery, the expression levels of Rho kinase 1 （ ROCK-1 ） and eNOS mRNA in lung tissue were also detected. Results All rats in the prevention protocol survived. Rosuvastatin treatment improved survival in the treatment protocol （58% , 75 % vs. 30% , P 〈 0. 05 ）. Rosuvastatin therapy in both preventment or treatment protocols significantly lowered mPAP [ prevention protocol ： （ 27.53 ± 3.43 ）, （ 25.72 ± 1.76 ） vs. （ 36. 05±2.45 ） mm Hg（ 1 mm Hg = 0. 133 kPa）, P 〈 0. 01 ; treatment protocol： （ 30. 39± 3.17 ）, （27.59 ± 1.99） vs. （40. 68 ± 1.39） mm Hg, P 〈 0. 01 ], reduced thickening of small pulmonary artery wall （ P 〈 0.01 ） and fight ventricular hypertrophy （ P 〈 0. 01 ）. Rosuvastatin also inhibited PCNA expression of SMC （ P 〈 0. 01 ） , restored eNOS expression of EC （ P 〈 0. 05 ） and inhibited ROCK-1 mRNA expressions in lung tissue （P 〈 0. 05 ）. Conclusions Rosuvastatin therapy reduced mPAP in monocrotaline-induced pulmonary arterial hypertension rat model and this effect is linked with inhibition of ROCK-1 expression, inhibition of smooth muscle cell proliferation and restoration of endothelial cell functions.