GADD45B inhibits MKK7-induced cardiac hypertrophy and the polymorphisms of GADD45B is associated with inter-ventricular septum hypertrophy.
Mitogen-activated protein kinase kinase 7 (MKK7) induces cardiac hypertrophy by activating the c-Juns NH2-terminal kinases (JNK). It has been reported that growth arrest and DNA-damage-inducible beta (GADD45Beta) binds to MKK7 directly and blocks its catalytic activity, mediates the inhibition of JNK signaling. However, the potential role of GADD45Beta on cardiac hypertrophy has not been investigated. In this study, we found co-infection of cardiomyocytes with adenoviral vectors expressing MKK7 and GADD45B could counteract the characteristic hypertropic responses, including an increase in cell size and elevated atrial natriuretic factor (ANP) expression which induced by overexpression of MKK7. Furthermore, siRNA-mediated knockdown of GADD45B could also cause cardiomyocytes hypertrophy. GeneChip data showed that GADD45B mRNA decreased significantly in patients with hypertrophy cardiomyopathy (HCM) compared with healthy subjects. Association study indicated that haplotype (rs2024144-rs3783501) of GADD45B affected the thickness of inter-ventricular septum in patients with HCM. Dual-luciferase assay showed that C-A haplotype displayed significantly increased transcription activity compared to T-G haplotype.
Sino-German Laboratory for Molecular Medicine, FuWai Cardiovascular Hospital and Cardiovascular Institute, Peking Union Medical College and Chinese Academy of Medical Sciences, 167 Beilishi Road, 100037 Beijing, China.
Jianwei
J
Wang
Hu
H
Wang
Jingzhou
J
Chen
Xiaojian
X
Wang
Kai
K
Sun
Yibo
Y
Wang
Jizheng
J
Wang
Xu
X
Yang
Xiaodong
X
Song
Ying
Y
Xin
Zhe
Z
Liu
Rutai
R
Hui
D000483:Alleles; D000818:Animals; D000943:Antigens, Differentiation / Q000235:genetics* / Q000378:metabolism*; D009320:Atrial Natriuretic Factor / Q000378:metabolism; D006332:Cardiomegaly / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D002478:Cells, Cultured; D004742:Enhancer Elements, Genetic; D017930:Genes, Reporter; D006239:Haplotypes; D006801:Humans; D048688:MAP Kinase Kinase 7 / Q000235:genetics / Q000378:metabolism; D032383:Myocytes, Cardiac / Q000378:metabolism / Q000473:pathology; D011110:Polymorphism, Genetic; D012333:RNA, Messenger / Q000378:metabolism; D034741:RNA, Small Interfering / Q000235:genetics; D051381:Rats; D014158:Transcription, Genetic; D054088:Ventricular Septum / Q000378:metabolism / Q000473:pathology*; D000097642:GADD45 Proteins
D000943:Antigens, Differentiation; D009320:Atrial Natriuretic Factor; D048688:MAP Kinase Kinase 7; D012333:RNA, Messenger; D034741:RNA, Small Interfering; C086470:GADD45B protein, human; D000097642:GADD45 Proteins; C482569:MAP2K7 protein, human