CAJ | 학술논문

目的探讨Survivin在慢性缺氧性肺动脉高压大鼠肺组织中的表达及意义.方法将18只雄性Wistar大鼠随机分为对照组(N组)、缺氧4周组(H组)、缺氧4周+YM155组(小分子Survivin 拮抗剂,HY组),每组6只,观察YM155对大鼠肺动脉平均压(mPAP)、右心室质量(RV)和左心室+室间隔质量(LV+S)的影响；采用免疫组织化学的方法,观察Survivin在三组大鼠肺组织中的表达及分布特点；采用实时定量PCR方法分析三组大鼠肺组织中Survivin mRNA的表达水平.结果 ①经YM155处理后,缺氧组大鼠mPAP从(29.4±1.7) mm Hg降至(19.6±1.3) mm Hg(P＜0.01),RV质量从(0.29±0.02)g降至(0.19±0.02)g(P＜0.01).②N组大鼠,无论是近端肺动脉,还是远端肺动脉,Survivin均不表达.而在H组,Survivin在肺内小动脉(直径60～200 μm)呈高表达(P＜0.01),且主要位于中膜,而在近端肺动脉,即中型肺动脉(200～500 μm)和大型肺动脉(500～1 000 μm),Survivin无明显表达.H组小型肺动脉Survivin的阳性表达强度(平均吸光度值,A值)较N组A值显著增加(N组:0.001 3±0.000 5 vs H组:0.268 3±0.023 9,P＜0.01).YM155处理后,HY组大鼠肺内小肺动脉Survivin的表达强度(A值)明显减弱(H组:0.268 3±0.023 9 vs HY组:0.001 8±0.000 4).③H组大鼠肺组织Survivin mRNA表达水平明显高于N组大鼠(P＜0.01),YM155处理后,HY组大鼠肺组织Survivin mRNA表达水平明显下降(P＜0.01).结论 Survivin在慢性缺氧肺组织中高表达,且主要位于肺内小动脉的中膜,小分子Survivin拮抗剂YM155可以降低mPAP、减轻右心室肥厚,逆转肺动脉高压,从而揭示Survivin可能是肺动脉高压的治疗新靶位.
목적 탐토Survivin재만성결양성폐동맥고압대서폐조직중적표체급의의.방법 장18지웅성Wistar대서수궤분위대조조(N조)、결양4주조(H조)、결양4주+YM155조(소분자Survivin 길항제,HY조),매조6지,관찰YM155대대서폐동맥평균압(mPAP)、우심실질량(RV)화좌심실+실간격질량(LV+S)적영향；채용면역조직화학적방법,관찰Survivin재삼조대서폐조직중적표체급분포특점；채용실시정량PCR방법분석삼조대서폐조직중Survivin mRNA적표체수평.결과 ①경YM155처리후,결양조대서mPAP종(29.4±1.7) mm Hg강지(19.6±1.3) mm Hg(P＜0.01),RV질량종(0.29±0.02)g강지(0.19±0.02)g(P＜0.01).②N조대서,무론시근단폐동맥,환시원단폐동맥,Survivin균불표체.이재H조,Survivin재폐내소동맥(직경60～200 μm)정고표체(P＜0.01),차주요위우중막,이재근단폐동맥,즉중형폐동맥(200～500 μm)화대형폐동맥(500～1 000 μm),Survivin무명현표체.H조소형폐동맥Survivin적양성표체강도(평균흡광도치,A치)교N조A치현저증가(N조:0.001 3±0.000 5 vs H조:0.268 3±0.023 9,P＜0.01).YM155처리후,HY조대서폐내소폐동맥Survivin적표체강도(A치)명현감약(H조:0.268 3±0.023 9 vs HY조:0.001 8±0.000 4).③H조대서폐조직Survivin mRNA표체수평명현고우N조대서(P＜0.01),YM155처리후,HY조대서폐조직Survivin mRNA표체수평명현하강(P＜0.01).결론 Survivin재만성결양폐조직중고표체,차주요위우폐내소동맥적중막,소분자Survivin길항제YM155가이강저mPAP、감경우심실비후,역전폐동맥고압,종이게시Survivin가능시폐동맥고압적치료신파위.
Objective To clarify the roles of Survivin in the chronic hypoxic pulmonary hypertension (HPH),the expression of Survivin was investigated in rats.Methods Eighteen age and body weight matched male Wistar rats were randomly divided into control,chronic hypoxic group for 4 weeks and chronic hypoxic group for 4 weeks treated with YM155 group.YM155 dose of 6.5 mg/kg filled the Alzet penetration capsules pump,under sterile conditions,the pump was implanted in rat abdominal subcutaneous continuous administration of the first and second weeks of hypoxia implanted each capsules.The expression and distribution of Survivin were examined along the axial pathway of the pulmonary arteries of three group rats using immunohistochemical method,and Survivin mRNA expression of lung tissue of three group rats was analyzed by real-time polymerase chain reaction.Results After treating with YM155,mPAP of hypoxia rats was declined from (29.4±1.7)mm Hg to (19.6±1.3)mm Hg (P ＜0.01),and the weight of RV from (0.29±0.02)g to (0.19±0.02)g (P ＜0.01).In normal condition,Survivin was not expressed in the pulmonary arteries both in the proximal and distal segments.Following exposure to hypoxia,the distribution of Survivin localized predominated in the media of the distal segments of pulmonary artery,whereas Survivin was not almost expressed in the intima of the distal segments (P ＜0.01).After treating with YM155,the expression of Survivin was down-regulated,especially in the media of the distal segments of pulmonary artery after four weeks exposure to chronic hypoxia (P ＜0.01).Under normoxic condition,the mRNA expression of Survivin in rat pulmonary tissues was not detected,after 4 weeks hypoxia,the mRNA expression of Survivin in pulmonary tissues was significantly increase.When treated with YM155,the mRNA expression of Survivin in hypoxic rat pulmonary tissues was remarkable decrease from (27 989.55± 15 130.29) to (5 406.11± 1 554.20).Conclusions Survivin was highly expressed in the pulmonary arteries of rats exposed to chronic hypoxia,its distribution in the media was in the distal segments.YM155,a novel small-molecule Survivin suppressant,could not only down-regulate expression of Survivin in the distal pulmonary artery and lung tissue of rats exposed to chronic hypoxia,but also reduce mPAP and RVH,and reverse HPH of the rats.YM155 might potentially be a therapeutic agent for HPH.