[1]杨文娟,张晓天,黄燕湖,等.TAZ蛋白在血管紧张素Ⅱ诱导的高血压小鼠主动脉纤维化中的作用及其机制[J].新乡医学院学报,2023,40(3):201-206.[doi:10.7683/xxyxyxb.2023.03.001]
　YANG Wenjuan,ZHANG Xiaotian,HUANG Yanhu,et al.Role and mechanism of TAZ in aortic fibrosis of angiotensin Ⅱ-induced hypertensive mice[J].Journal of Xinxiang Medical University,2023,40(3):201-206.[doi:10.7683/xxyxyxb.2023.03.001]
点击复制

TAZ蛋白在血管紧张素Ⅱ诱导的高血压小鼠主动脉纤维化中的作用及其机制
分享到：

《新乡医学院学报》[ISSN:1004-7239/CN:41-1186/R]

卷:
40卷
期数:
2023年3期
页码:
201-206
栏目:
基础研究
出版日期:
2023-03-05

文章信息/Info

Title:
Role and mechanism of TAZ in aortic fibrosis of angiotensin Ⅱ-induced hypertensive mice
作者:
杨文娟1; 张晓天1; 黄燕湖1; 姚　阳2; 屈晓萌1; 周明生2; 徐茜2
（1.沈阳医学院基础医学院，辽宁　沈阳　110034；2.沈阳医学院科学实验中心，辽宁　沈阳　110034）
Author(s):
YANG Wenjuan1; ZHANG Xiaotian1; HUANG Yanhu1; YAO Yang2; QU Xiaomeng1; ZHOU Mingsheng2; XU Qian2
（1.Basic Medical College,Shenyang Medical College,Shenyang 110034,Liaoning Province,China；2.Scientific Experiment Center,Shenyang Medical College,Shenyang 110034,Liaoning Province,China）
关键词:
PDZ结合域的转录共刺激因子; 血管紧张素Ⅱ; 高血压; 纤维化; 维替泊芬
Keywords:
transcriptional co-activator with PDZ-binding motif; angiotensin Ⅱ; hypertension; fibrosis; verteporfin
分类号:
R363.2
DOI:
10.7683/xxyxyxb.2023.03.001
文献标志码:
A
摘要:
目的探讨PDZ结合域的转录共刺激因子（TAZ）蛋白在血管紧张素Ⅱ(AngⅡ)诱导的高血压小鼠主动脉纤维化中的作用及其机制。
方法将18只雄性C57BL/6小鼠随机分为正常对照组、AngⅡ组和AngⅡ+维替泊芬（Ve）组，每组6只。Ang Ⅱ 组和 Ang Ⅱ+ Ve 组小鼠皮下植入注满Ang Ⅱ 的渗透压微量泵，持续14 d释放Ang Ⅱ（1.1 mg·kg-1·d-1）诱导小鼠高血压模型；正常对照组小鼠不进行AngⅡ干预。AngⅡ+Ve组小鼠隔日腹腔注射1次Ve（60 mg·kg-1）至实验结束；AngⅡ组和正常对照组小鼠隔日腹腔注射等量生理盐水。造模结束后，采用尾动脉测压法测定小鼠收缩压（SBP）、舒张压（DBP）和心率；使用水合氯醛麻醉小鼠，打开胸腔，分离主动脉，采用苏木精-伊红染色法检测小鼠主动脉厚度，Masson 染色法检测小鼠主动脉纤维化情况，Western blot法检测TAZ、转化生长因子-β（TGF-β）、母亲信号蛋白同源物3(Smad3)、磷酸化母亲信号蛋白同源物3(p-Smad3)和Ⅰ型胶原蛋白（collagen Ⅰ）表达。
结果3组小鼠SBP、DBP比较差异有统计学意义（F=79.900、40.650，P<0.05）。AngⅡ组和AngⅡ+Ve组小鼠SBP、DBP显著高于正常对照组，AngⅡ+Ve组小鼠SBP、DBP显著低于AngⅡ组（P<0.05）。3组小鼠心率比较差异无统计学意义（F=0.090，P>0.05）。 3组小鼠主动脉壁厚度比较差异有统计学意义（F=6.791，P<0.05）；Ang Ⅱ 组小鼠主动脉壁厚度显著高于正常对照组（t=3.435，P<0.05），Ang Ⅱ+Ve组小鼠主动脉壁厚度显著低于Ang Ⅱ组（t=2.598，P<0.05），Ang Ⅱ+Ve组与正常对照组小鼠主动脉壁厚度比较差异无统计学意义（t=0.361，P>0.05）。3组小鼠主动脉壁胶原纤维面积百分比比较差异有统计学意义（F=357.700，P<0.05）。Ang Ⅱ 组和Ang Ⅱ+Ve组小鼠主动脉壁胶原纤维面积百分比显著高于正常对照组（t=25.810、4.882，P<0.05），Ang Ⅱ+Ve组小鼠主动脉壁胶原纤维面积百分比显著低于Ang Ⅱ 组（t=20.580，P<0.05）。Ang Ⅱ 组小鼠主动脉中TAZ、TGF-β、p-Smad3、collagen Ⅰ蛋白相对表达量显著高于正常对照组（P<0.05）；Ang Ⅱ+Ve组小鼠主动脉中TAZ、TGF-β、p-Smad3、collagen Ⅰ蛋白相对表达量显著低于Ang Ⅱ 组（P<0.05）； Ang Ⅱ+Ve组小鼠主动脉中TGF-β蛋白相对表达量显著高于正常对照组（P<0.05），TAZ、p-Smad3、collagen Ⅰ蛋白相对表达量与正常对照组比较差异无统计学意义（P>0.05）。3组小鼠主动脉中Smad3蛋白相对表达量比较差异无统计学意义（F=46.010,P>0.05）。
结论TAZ可通过增加纤维化相关蛋白p-Smad3及collagen Ⅰ表达，激活 Hippo通路，促进Ang Ⅱ 诱导的高血压小鼠主动脉增生和纤维化。
Abstract:
ObjectiveTo investigate the role and mechanism of transcriptional co-activator with PDZ-binding motif (TAZ) in angiotensin Ⅱ(Ang Ⅱ)-induced hypertensive mice.MethodsEighteen male C57BL/6 mice were randomly divided into normal control group,AngⅡ group,AngⅡ+verteporfin (Ve) group,with six mice in each group.The mice in the AngⅡ group and AngⅡ+Ve group were subcutaneously implanted with osmotic pressure micropump filled with AngⅡ,and AngⅡ (1.1 mg·kg-1·d-1) was released for 14 days to induce hypertension models.The mice in the normal control group were not treated with AngⅡ.The mice in the AngⅡ+Ve group were intraperitoneally injected with Ve (60 mg·kg-1),every other day,until the end of the experiment.The mice in the AngⅡ group and normal control group were intraperitoneally injected with same amount of saline,every other day.After modeling,the systolic blood pressure(SBP),diastolic blood pressure(DBP) and heart rate of mice were measured by tail artery method;the mice were anesthetized with chloral hydrate,the thoracic cavity was opened,the aorta was isolated,and the thickness of aorta of the mice was measured by hematoxylin-eosinstaining,the condition of the fibrosis of aorta of mice was detected by Masson staining,and the expressions of TAZ,transforming growth factor-β(TGF-β),mothers against decapentaplegic homolog 3 (Smad3),phosphorylated mothers against decapentaplegic homolog 3 (p-Smad3) and collagen Ⅰ (collagen Ⅰ) were detected by Western blot.ResultsThere were significant differences in SBP and DBP of mice among the three groups (F=79.900,40.650;P<0.05).The SBP and DBP of mice in the Ang Ⅱ group and Ang Ⅱ+Ve group were significantly higher than those in the normal control group,the SBP and DBP of mice in the Ang Ⅱ+Ve group were significantly lower than those in the Ang Ⅱ group (P<0.05).There was no significant difference in heart rate of mice among the three groups(F=0.090,P>0.05).There was significant difference in the thickness of aortic wall of mice among the three groups (F=6.791,P<0.05);the thickness of aortic wall of mice in the Ang Ⅱ group was significantly higher than that in the normal control group (t=3.435,P<0.05),and the thickness of aortic wall of mice in the Ang Ⅱ+Ve group was significantly lower than that in the Ang Ⅱ group (t=2.598,P<0.05),there was no significant difference in the thickness of aortic wall of mice between the Ang Ⅱ+Ve group and normal control group (t=0.361,P>0.05).There was significant difference in the percentage of collagen fiber area in the aortic wall of mice among the three groups (F=357.700,P<0.05).The percentage of collagen fibers area in the aortic wall of mice in the Ang Ⅱ group and Ang Ⅱ+Ve group was significantly higher than that in the normal control group (t=25.810,4.882;P<0.05),and the percentage of collagen fibers area in the aortic wall of mice in the Ang Ⅱ+Ve group was significantly lower than that in the Ang Ⅱ group(t=20.580,P<0.05).The relative expressions of TAZ,TGF-β,p-Smad3 and collagen Ⅰ protein in aorta of mice in the Ang Ⅱ group were significantly higher than those in the normal control group (P<0.05);the relative expressions of TAZ,TGF-β,p-Smad3 and collagen Ⅰ protein inaorta of mice in the Ang Ⅱ+Ve group were significantly lower than those in the Ang Ⅱ group (P<0.05);the relative expression of TGF-β protein in aorta of mice in theAng Ⅱ+Ve group was significantly higher than that in the normal control group (P<0.05);there was no significant difference in the relative expressions of TAZ,p-Smad3,collagen Ⅰ protein in aorta of mice between the Ang Ⅱ+Ve group and normal control group (P>0.05).There was no significant difference in the relative expression of Smad3 protein in aorta of mice among the three groups （F=46.010,P>0.05）.Conclusion　TAZ can activate Hippo pathway by increasing the expression of fibrosis-associated protein p-Smad3 and collagen Ⅰ,and promote aortic proliferation and fibrosis in Ang Ⅱ -induced hypertensive mice.

参考文献/References:

［1］　骆雷鸣,任金霞.高血压心脏形态、结构改变及危害［J］.中华保健医学杂志,2021,23(6):555-560.
LUO L M,REN J X.Hypertensive cardiac morphology,structural changes and hazards［J］.Chin J Health Care Med,2021,23(6):555-560.
［2］　崔伟锋,刘萧萧,韩静旖,等.原发性高血压病心血管风险因素分析［J］.中国全科医学,2020,23(22):2797-2803.
CUI W F,LIU X X,HAN J Y,et al.The risk factors of cardiovascular disease in patients with essential hypertension［J］.Chin Gener Pract,2020,23(22):2797-2803.
［3］　MA S,MENG Z,CHEN R,et al.The Hippo pathway:biology and pathophysiology［J］.Annu Rev Biochem,2019,88:577-604.
［4］　顾燕妮,谢春毅.Hippo信号通路与心脏病［J］.国际心血管病杂志,2021,48(5):281-284.
GU Y N,XIE C Y.Hippo signaling pathway and heart disease［J］.Int J Cardiovasc Dis,2021,48(5):281-284.
［5］　王永煜,余薇,周斌.Hippo信号通路与心血管发育及疾病调控［J］.遗传,2017,39(7):576-587.
WANG Y Y,YU W,ZHOU B.Hippo signaling pathway in cardiovascular development and diseases［J］.Hereditas,2017,39(7):576-587.
［6］　ZHENG A,CHEN Q,ZHANG L.The Hippo-YAP pathway in various cardiovascular diseases:focusing on the inflammatory response［J］.Front Immunol,2022,13:971416.
［7］　TE RIET L,VAN ESCH J H,ROKS A J,et al.Hypertension:renin-angiotensin-aldosterone system alterations［J］.Circ Res,2015,116(6):960-975.
［8］　VIGNESWARAN K,BOYD N H,OH S Y,et al.YAP/TAZ transcriptional coactivators create therapeutic vulnerability to verteporfin in EGFR-mutant glioblastoma［J］.Clin Cancer Res,2021,27(5):1553-1569.
［9］　卓坤萍,姚阳,周明生,等.TAZ蛋白在血管紧张素Ⅱ诱导的人脐静脉内皮细胞MCP-1表达中的作用研究［J］.中国继续医学教育,2022,14(17):190-194.
ZHUO K P,YAO Y,ZHOU M S,et al.The role of TAZ in angiotensin Ⅱ-induced MCP-1 expression in human umbilical vein endothelial cells［J］.Chin Contin Med Edu,2022,14(17):190-194.
［10］　GUZIK T J,TOUYZ R M.Oxidative stress,inflammation,and vascular aging in hypertension［J］.Hypertension,2017,70(4):660-667.
［11］　张玉,马亮亮,张海垠.动脉粥样硬化性心血管疾病与H型高血压的关系研究［J］.中国医药,2018,13(11):1620-1623.
ZHANG Y,MA L L,ZHANG H Y.Relationship between atherosclerotic cardiovascular disease and H-type hypertension［J］.Chin Med,2018,13(11):1620-1623.
［12］　LOW E L,BAKER A H,BRADSHAW A C.TGFβ,smooth muscle cells and coronary artery disease:a review［J］.Cell Signal,2019,53:90-101.
［13］　PETRIE J R,GUZIK T J,TOUYZ R M.Diabetes,hypertension,and cardiovascular disease:clinical insights and vascular mechanisms［J］.Can J Cardiol,2018,34(5):575-584.
［14］　POASAKATE A,MANEESAI P,POTUE P,et al.Genistein alleviates renin-angiotensin system mediated vascular and kidney alterations in renovascular hypertensive rats［J］.Biomed Pharmacother,2022,146:112601.
［15］　CHOUDHARY R,SHREE J,SINGH A,et al.Role of the reni-nangiotensin system in the development of cataract formation in angiotensin-Ⅱ-induced experimental rats［J］.J Biochem Mol Toxicol,2021,35(7):e22789.
［16］　EGUCHI S,DEMPSEY P J,FRANK G D,et al.Activation of MAPKs by angiotensin Ⅱ in vascular smooth muscle cells.Metalloprotease-dependent EGF receptor activation is required for activation of ERK and p38 MAPK but not for JNK［J］.J Biol Chem,2001,276(11):7957-7962.
［17］　CAO X,LUO T,LUO X,et al.Resveratrol prevents Ang Ⅱ-induced hypertension via AMPK activation and RhoA/ROCK suppression in mice［J］.Hypertens Res,2014,37(9):803-810.
［18］　GUO R W,YANG L X,WANG H,et al.Angiotensin II induces matrix metalloproteinase-9 expression via a nuclear factor-kappaB-dependent pathway in vascular smooth muscle cells［J］.Regul Pept,2008,147(1-3):37-44.
［19］　POJER J M,MANNING S A,KROEGER B,et al.The Hippo pathway uses different machinery to control cell fate and organ size［J］.iScience,2021,24(8):102830.
［20］　NOGUCHI S,SAITO A,NAGASE T.YAP/TAZ signaling as a molecular link between fibrosis and cancer［J］.Int J Mol Sci,2018,19(11):3674.
［21］　李晶晶.Hippo信号通路与皮肤组织细胞修复研究进展［J］.中国美容医学,2020,29(1):162-165.
LI J J.Advances of Hippo signaling pathway and skin tissue cell repair［J］.Chin J Aesth Med,2020,29(1):162-165.
［22］　WANG L,LUO J Y,LI B,et al.Integrin-YAP/TAZ-JNK cascade mediates atheroprotective effect of unidirectional shear flow［J］.Nature,2016,540(7634):579-582.
［23］　PICCOLO S,DUPONT S,CORDENONSI M.The biology of YAP/TAZ:hippo signaling and beyond［J］.Physiol Rev,2014,94(4):1287-1312.
［24］　WENNMANN D O,VOLLENBROKER B,ECKART A K,et al.The Hippo pathway is controlled by angiotensin Ⅱ signaling and its reactivation induces apoptosis in podocytes［J］.Cell Death Dis,2014,5(11):e1519.
［25］　DUPONT S,MORSUT L,ARAGONA M,et al.Role of YAP/TAZ in mechanotransduction［J］.Nature,2011,474(7350):179-183.

相似文献/References:

[1]张庆超,李玉春.高血压病患者血清Ⅲ型前胶原和血管紧张素Ⅱ水平及苯那普利的干预作用[J].新乡医学院学报,2003,20(05):332.
[2]贺国洋,李巍,冶亚平,等.血管紧张素Ⅱ对人脐静脉内皮细胞凋亡的影响[J].新乡医学院学报,2009,26(03):257.
[3]杨　莉,贺　静,孙晓慧,等.MicroRNA-185对血管紧张素Ⅱ介导的心肌细胞肥大和凋亡的影响[J].新乡医学院学报,2019,36(11):1024.[doi:10.7683/xxyxyxb.2019.11.005]
　YANG Li,HE Jing,SUN Xiao-hui,et al.Effect of microRNA-185 on angiotensin Ⅱ mediated cardiomyocyte hypertrophy and apoptosis[J].Journal of Xinxiang Medical University,2019,36(3):1024.[doi:10.7683/xxyxyxb.2019.11.005]

更新日期/Last Update: 2023-03-05