视黄醇结合蛋白1通过激活TAK1促进大鼠乳鼠原代心肌细胞肥大  

Retinol binding protein 1 promotes hypertrophy of primary neonatal rat cardiomyocytes via activating TAK1

作　　者：谢菁[1] 周艳丽[1] 陈思思[1] 王继春[1] 江洪[1] XIE Jing;ZHOU Yanli;CHEN Sisi;WANG Jichun;JIANG Hong(Department of Cardiology,Renmin Hospital of Wuhan University,Cardiovascular Research Institute,Wuhan University,Hubei Key Laboratory of Cardiology,Wuhan 430000,China)

机构地区：[1]武汉大学人民医院心血管内科,武汉大学心血管病研究所,心血管病湖北省重点实验室,湖北武汉430000

出　　处：《中国病理生理杂志》2023年第2期233-240,共8页Chinese Journal of Pathophysiology

基　　金：中央高校基本科研业务费专项资金青年教师资助项目(No.2042019kf0093)。

摘　　要：目的:探究视黄醇结合蛋白1(retinol binding protein 1, Rbp1)在大鼠乳鼠原代心肌细胞肥大中的功能和机制。方法:本研究通过联合分析基因表达数据库(Gene Expression Omnibus, GEO)中的小鼠心肌肥厚基因芯片数据,寻找在心肌肥厚发生过程中的关键调控因子,构建该基因过表达及敲减腺病毒并感染大鼠乳鼠原代心肌细胞,利用血管紧张素II(angiotensin II, Ang II)诱导大鼠乳鼠原代心肌细胞肥大模型,研究目的基因对大鼠乳鼠原代心肌细胞肥大的影响,应用Western blot及RT-qPCR探究目的基因调控大鼠乳鼠原代心肌细胞肥大的分子机制。结果:在小鼠心肌肥厚心脏组织中Rbp1的表达显著上调(P<0.01),体外细胞实验显示与对照组相比,Rbp1过表达组的大鼠乳鼠原代心肌细胞面积显著增大,心肌肥厚标志基因心钠肽(atrial natriuretic peptide, Anp)和肌球蛋白重链7(myosin heavy chain 7, Myh7)的表达显著升高(P<0.01),证实Rbp1过表达能促进Ang II诱导的大鼠乳鼠原代心肌细胞肥大;相反,Rbp1敲减则能显著抑制Ang II诱导的大鼠乳鼠原代心肌细胞面积增加和心肌肥厚标志物表达。机制研究显示,Rbp1过表达显著激活转化生长因子β激活激酶1(transforming growth factor-β-activated kinase 1, TAK1)和P38(P<0.01),应用TAK1抑制剂可阻断Rbp1过表达对Ang II诱导大鼠乳鼠原代心肌细胞肥大的促进作用。结论:Rbp1可通过激活TAK1信号通路促进Ang II诱导的大鼠乳鼠原代心肌细胞肥大。AIM: To investigate of the function and mechanism of retinol binding protein 1(Rbp1) in the hypertrophy of primary neonatal rat cardiomyocytes. METHODS: The microarray data from Gene Expression Omnibus(GEO) database was analyzed to identify the key regulatory factors in the process of cardiac hypertrophy. In order to explore the function of the key gene in the hypertrophy induced by angiotensin II(Ang II), overexpression and knockdown adenoviruses were constructed to infect primary neonatal rat cardiomyocytes. Western blot and RT-qPCR were used to explore the mechanism of the key gene regulating hypertrophy of primary neonatal rat cardiomyocytes. RESULTS: The expression of Rbp1 was significantly up-regulated(P<0. 01) in the heart of mouse cardiac hypertrophy models. Moreover, in vitro experiments showed that compared with control group, the area of primary neonatal rat cardiomyocytes and the expression of cardiac hypertrophy marker gene atrial natriuretic peptide(Anp) and myosin heavy chain 7(Myh7) was significantly increased in Rbp1 overexpression group, indicating that overexpression of Rbp1 promotes Ang II-induced primary neonatal rat cardiomyocytes hypertrophy. On the contrary, knockdown of Rbp1 dramatically inhibited the increase in primary neonatal rat cardiomyocyte area and the expression of cardiac hypertrophy markers induced by Ang II. Overexpression of Rbp1 activated transforming growth factor-β-activated kinase 1(TAK1) and its downstream target P38(P<0. 01). Treatment with TAK1 inhibitor blocked the effect of Rbp1 overexpression on Ang II-induced primary neonatal rat cardiomyocyte hypertrophy. CONCLUSION: The Rbp1 promotes Ang II-induced primary neonatal rat cardiomyocyte hypertrophy by activating the TAK1/P38 signaling pathway.

关 键 词：视黄醇结合蛋白1 大鼠乳鼠原代心肌细胞 心肌肥大 TAK1/P38信号通路 

分 类 号：R541.6[医药卫生—心血管疾病] R363.2[医药卫生—内科学]