丝裂原活化蛋白激酶调节缺氧诱导因子1α对大鼠缺氧性肺动脉高压的作用  

Mitogen-activated protein kinase regulated hypoxia-inducible factor 1α in hypoxia-induced pulmonary hypertension in rats

作　　者：孔春初 戴爱国 

机构地区：[1]湖南省老年医院湖南省老年医学研究所呼吸疾病研究室,长沙410001

出　　处：《中华结核和呼吸杂志》2005年第5期328-332,共5页Chinese Journal of Tuberculosis and Respiratory Diseases

基　　金：国家自然科学基金资助项目(30270581);湖南省教育厅重点科研基金资助项目(02A047);中国博士后科学基金资助项目(2003033436);教育部科学技术研究重点项目(03091)

摘　　要：目的探讨丝裂原活化蛋白激酶(MAPK)和缺氧诱导因子1α(HIF-1α)的表达变化在缺氧性肺动脉高压(HPH)中的作用和意义。方法40只成年雄性Wistar大鼠随机分为对照组(C组)和低氧3、7、14、21d组(H3、H7、H14、H21组),每组8只,低氧组复制HPH大鼠模型。测各组大鼠平均肺动脉压(mPAP)、右室肥大指数(RVHI)、血管形态学指标;Westernblot或免疫组化检测磷酸化细胞外信号调节激酶(pERK)、磷酸化cJUN氨基端蛋白激酶(pJNK)、磷酸化P38(pP38);原位杂交和免疫组化检测HIF1α的表达。结果(1)H7组大鼠mPAP、管壁厚度与血管外径比值及管壁面积与血管面积比值分别为(23.5±1.8)mmHg、(45.5±3.1)%和(54.7±3.2)%,与C组[(16.2±2.0)mmHg、(36.8±2.5)%和(63.2±2.5)%]比较差异均有统计学意义(P均<0.05),H14组稳定于高水平;H14组RVHI为(26.5±2.9)%,与C组[(22.9±2.2)%]比较差异也有统计学意义(P<0.05);(2)pERK蛋白在C组表达不明显,在H3组表达上升,与C组比较差异有统计学意义(P<0.05),且在H3、H7、H14、H21组肺小动脉内膜、中膜表达均为阳性。而pJNK、pP38蛋白在C组与H组表达均不明显;(3)C组HIF1α蛋白表达不明显,H3、H7、H14、H21组肺血管内膜均为阳性,肺血管中膜在H3组表达开始升高(0.209±0.009),与C组比较差异有统计学意?Objective To investigate the dynamic expression of hypoxia-inducible factor 1α(HIF-1α) and mitogen-activated protein kinase(MAPK) in pulmonary arteries of rats with hypoxia-induced pulmonary hypertension. Methods Forty male adult Wistar rats were randomly divided into five groups:a control group(C group) and groups with hypoxia for 3,7,14 and 21 days(H 3,H 7,H 14 and H 21 group),eight rats per group. Mean pulmonary pressure(mPAP),right ventrical hypertrophy index(RVHI) and vessel morphometry were measured. The levels of HIF-1α mRNA expression in lung tissue was measured by in site hybridization(ISH). The protein expression of HIF-1α and p-ERK,p-JNK,p-P38 were observed by immunohistochemistry or Western blot. Results The level of mPAP[(23.5±1.8)mm Hg],the ratio of vascular wall thickness to external diameter[WT,(45.5±3.1)%] and the ratio of vascular wall area to the total area[LA,(54.7±3.2)%] were significantly higher in H 7 group than those in C group[(16.2±2.0)mm Hg,(36.8±2.5)% and (63.2±2.5)% respectively,all P<0.05]. These parameters reached a high level and remained stable on H 14 group,RVHI was significantly higher[(26.9±1.3)%] on H 14 group than in C group[(23.0±1.5)%,P<0.05]. Expression of p-ERK protein in C group was barely positive,but was up-regulated in pulmonary arterial tunica intima and tunica media of all hypoxia rats. Expression of p-JNK and p-P38 in C group and hypoxia groups were barely positive. Expression of HIF-1α protein in C group was barely positive,but was up-regulated in pulmonary arterial tunica intima of all hypoxic rats. In pulmonary arterial tunica media,the levels of HIF-1α protein was markedly up-regulated in H 3 group(0.209±0.009, P<0.05),reaching its peak at H 7 group(0.232±0.008,P<0.05),then tended to decline in H 14 group and H 21 group. HIF-1α mRNA staining was barely positive in C group,H 3 group and H 7 group,but began to increase significantly at H 14 group(0.305±0.104,P<0.05),then remained stable in pulmonary arterial tunica intima. Linear correlation ana

关 键 词：丝裂原活化蛋白激酶 缺氧性肺动脉高压 缺氧诱导因子1Α 细胞外信号调节激酶 p-ERK Wistar大鼠 HIF-1Α蛋白 免疫组化检测 Western 平均肺动脉压 蛋白表达 mRNA 形态学指标 c-JUN 统计学 P38蛋白 动脉血管壁 HPH 磷酸化 

分 类 号：R543[医药卫生—心血管疾病]