5-羟基癸酸盐对低氧肺动脉高压大鼠肺血管重建的影响及其机制  

Effect and mechanism of 5-HD on pulmonary vascular remodeling of hypoxic pulmonary hypertension in rats

作　　者：董莉[1] 朱海萍[1] 李云雷[1] 李秋[1] 陈成水[1] 

机构地区：[1]温州医学院附属第一医院呼吸内科,浙江温州325000

出　　处：《温州医学院学报》2010年第5期445-449,共5页Journal of Wenzhou Medical College

基　　金：浙江省自然科学基金资助项目(Z208100)

摘　　要：目的:探讨线粒体ATP敏感性钾通道抑制剂(5-羟基癸酸盐,简称5-HD)对慢性低氧肺动脉高压大鼠肺动脉血管重建的影响及其机制。方法:雄性SD大鼠24只,随机分为正常组、低氧+PBS组、低氧+5-HD组(5mg·kg-1·d-1)(n=8)。采用常压间断低氧法建立大鼠低氧肺动脉高压模型。大鼠在慢性低氧1周后,每天皮下注射5-HD一次,共3周,对照组置于同一实验室内。4周后右心导管法检测肺动脉平均压(mPAP),颈总动脉插管测颈动脉平均压(mCAP),称取右室(RV)和左室+室间隔(LV+S)的重量,以RV/(LV+S)比值比来反映右心室重量的变化。光镜下结合图像分析软件测定肺小动脉相对中膜厚度(PAMT),透射电镜观察肺细小动脉超微结构的变化,免疫组织化学染色检测肺小动脉平滑肌骨架蛋白α-actin表达,反映肺血管重建情况。酶标仪法检测肺组织匀浆Caspase9、Caspase3酶活性,反映肺血管凋亡情况。结果:①低氧+PBS组mPAP、RV/(LV+S)、PAMT、α-actin含量显著高于正常组(P<0.05);低氧+5-HD组mPAP、RV/(LV+S)、PAMT、α-actin含量显著低于低氧+PBS组,但高于正常组(P<0.05),mCAP三组间差异无显著性;②透射电镜显示低氧+PBS组肺小动脉内皮细胞肿胀,竖状突起,凸向管腔,与基底膜相连处有大量空泡,内弹力板高度扭曲,粗细不均匀,部分区域结构不清甚至断裂,胶原纤维增多,中膜平滑肌细胞增生、肿胀。低氧+5-HD组内皮细胞形态规则,中膜平滑肌层变薄,胶原纤维明显减少,弹力板基本正常;③低氧+5-HD组大鼠肺小动脉平滑肌细胞胞浆线粒体Caspase9酶活性、Caspase3酶活性显著低于正常组,但显著高于低氧+PBS组(P<0.05)。结论:①肺动脉平滑肌细胞线粒体凋亡途径在低氧所致肺动脉高压肺动平滑肌层重构中起重要作用。②5-HD可能有逆转慢性低氧引起的肺血管重建的作用。Objective：To investigate the effect and mechanism of mitochondrial ATP-sensitive potassium channel（MitoKATP）inhibitor（5-hydroxydecanoate,5-HD） on pulmonary vascular remodeling in rats with hypoxic pulmonary hypertension（HPH）.Methods：Twenty-four Sprague-Dawley rats（♂）were randomly divided into three groups：normal control group（N）,chronic hypoxic plus PBS group（CH＋PBS）,chronic hypoxic plus 5-HD（5 mg·kg^-1·d^-1（）CH＋5-HD）group（n =8）.The HPH rats were estab-lished in intermittent normobaric hypoxic environment for four weeks.After hypoxia for 1 week,the CH＋5-HD group were injected with 5-HD（5 mg·kg^-1·d^-1,i.h.） half an hour before placed into hypoxic chamber,other conditions were similar to the CH＋PBS group.Mean pulmonary artery pressure（mPAP）,mean carotid pressure（mCAP）,right ventricular hypertrophy index[RV/（LV＋S）] were mearsured in each group.The pulmonary vascular remodeling was observed under light microscope combined with image analyzed soft ware to estimate the relative pulmonary artery medial thickness（PAMT）.The ultrastructural changes of pulmonary arterioles were observed under transmission electron microscope.Microplate Reader detected the Caspase 9 and Caspase 3 enzymatic activity of lung homogenate that reflect apoptosis.Results：①The mPAP、RV/（LV＋S）、PAMT and the mean density of α-Actin in CH＋PBS group were significantly higher than those in the N group（P〈0.05）,were significantly lower than those in the CH＋PBS group（P〈0.05）.Differences of mCAP among three groups were not significant（P〈0.05）.②In CH＋PBS group,Endothelial cell damage,distinct internal elastic plate distortion,vacuolization,collagen fiber proliferation were found under transmission electron microscopy.③The activity of Caspase 9,Caspase 3 in CH＋5-HD group were significantly lower than those in the N group（P〈0.05）,were significantly higher than in the CH＋PBS group（P〈0.05）.Conclusions：①Mitochon-drial-dependen

关 键 词：5-羟基癸酸盐 缺氧 高血压 肺性 线粒体ATP敏感钾通道 疾病模型 动物 大鼠 

分 类 号：R543.2[医药卫生—心血管疾病]