慢性低氧性肺动脉高压大鼠肺组织肾上腺髓质素-2的变化

CHANGES OF ADRENOMEDULLIN 2/INTERMEDIN IN THE LUNG OF RATS WITH CHRONIC HYPOXIC PULMONARY HYPERTENSION

目的:研究新的小分子生物活性肽肾上腺髓质素-2(ADM2/IMD)及其受体在慢性低氧性肺动脉高压大鼠肺组织中的变化和可能的作用。方法:SD大鼠随机分成2组(n=10):正常对照(NC)组和低氧四周(4H)组;放射免疫法测定血浆和肺组织ADM2/IMD和肾上腺素髓质素(ADM)蛋白水平;逆转录-多聚酶链反应(RT-PCR)法测定肺组织ADM2/IMD、ADM及其受体(CRLR,RAMP1、2、3)mRNA表达;免疫组化法测定ADM2/IMD在肺细小动脉的定位表达。结果:①4H组平均肺动脉压(mPAP)、右心室与左心室加室间隔重量比[RV/(LV+S)]高于NC组(P均<0.01)。②4H组血浆和肺组织匀浆ADM水平分别为NC组的2.3倍和3.2倍(P均<0.01),ADM2/IMD水平分别比NC组高89.6%和45.0%(P分别<0.01、<0.05)。③4H组肺组织ADM2/IMD与ADM mRNA表达高于NC组(P分别<0.01、<0.05),CRLR和RAMP1mRNA表达显著低于NC组(P均<0.01),而RAMP2和RAMP3mRNA表达水平两组间差异无显著性。④ADM2/IMD主要在大鼠肺细小动脉内皮细胞及血管外膜表达。结论:ADM2/IMD与ADM相似,与大鼠慢性低氧性肺动脉高压病理过程密切相关;ADM2/IMD及其受体CRLR/RAMP1基因表达和/或蛋白合成、代谢的改变可能参与了大鼠慢性低氧性肺动脉高压的发生发展。

To investigate the changes and probable roles of adrenomedullin2/intermedin （ADM2/IMD）, a novel micromolecular bioactive peptide, in the lungs of rats with chronic hypoxic pulmonary hypertension. Methods： Twenty male SD rats were randomly divided into normal control group（NC） and normobaric hypoxia group（4H）. The protein levels of ADM and ADM2/IMD in the plasma and lung were measured by radioimmunoassay and immunohistochemistry. The mRNA expressions of ADM, ADM2/IMD and their receptors CRLR, RAMP1, RAMP2 and RAMP3 in the lung tissue were determined by reverse transeription-polymerase chain reaction（RT-PCR）. Results： OThe rat model of chronic pulmonary hypertension was confirmed by the increased mean pulmonary arterial pressure （mPAP） and weight ratio of right ventricle to left ventricle plus septum[RV/（LV＋ S）] in 4H group compared to NC group. （2） The concentrations of ADM in the plasma and lung homogenate of 4H group were 2.3 and 3.2 folds of NC group, respectively（all P 〈0.01）. The levels of ADM2/IMD were higher 89.6% and 45.0% in the plasma and lung homogenate of 4H group than those of NC group（respectively, P 〈0.01, P〈0.05）. （3） The mRNA expressions of ADM2/IMD and ADM in the lung of 4H group were up-regulated （respectively, P〈0.01, P〈0.05 vs NC group）. The expressions of CRLR and RAMP1 mRNAs were down-regulated（all P〈0.01 vs NC group）, while the levels of RAMP2 and RAMP3 mRNAs were no significant difference between the two groups. （4） The strong ADM2/IMD immunostaining was detected in the endothelial and adventitial cells of the rat pulmonary arteriole.Conclusion： ADM2/IMD, like its paralog ADM, might be tic, ely related to the chronic hypoxic pulmonary hypertension in rats. The disoMers of the gene expression and/or the synthesis and metabolism of ADM2/IMD and its receptor CRLR/RAMP1 possibly take part in the pathogenesis of chronic hypoxic pulmonary hypertension in rats.