The Human Myotrophin Variant Attenuates MicroRNA-Let-7 Binding Ability but Not Risk of Left Ventricular Hypertrophy in Human Essential Hypertension.
Myotrophin, known as a myocardial hypertrophy-inducing factor, is responsible for the initiation of cardiac hypertrophy that transits to heart failure. MicroRNAs are small noncoding RNAs that down-regulate posttranscriptional expression of target molecules. We investigated the role of variants of the microRNA-binding site in myotrophin in affecting its expression and any association with cardiac hypertrophy. Bioinformatics demonstrated that variant rs17168525 was identified to be located in the let-7/miR-98-binding site of myotrophin. We further experimentally test to effects of the identified variant on myotrophin translation using luciferase reporter assay and Western blotting. We found that the C allele of rs17168525 suppressed myotrophin translation by facilitating let-7c binding, but not the T allele. Let-7c overexpression caused a significant decrease in the level of myotrophin protein. Next, we investigated the association of the variant with cardiac hypertrophy in 1614 hypertensive patients, including 552 with left ventricular hypertrophy and 1062 without left ventricular hypertrophy, as well as 591 healthy control subjects from a Han Chinese population. No significant association between the variant rs17168525 and left ventricular hypertrophy in hypertensive patients in a Han Chinese population (P>0.05). In conclusion, our experimental results provide evidence that the T allele of rs17168525 in the 3'-UTR of myotrophin might influence the level of myotrophin protein by interfering with let-7/miR-98 binding.
Department of Biochemistry and Molecular Biology, Shanxi Medical University, Taiyuan, China; Sino-German Laboratory for Molecular Medicine, State Key Laboratory of Cardiovascular Disease, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
Yuyao
Y
Wang
Sino-German Laboratory for Molecular Medicine, State Key Laboratory of Cardiovascular Disease, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
Jingzhou
J
Chen
Sino-German Laboratory for Molecular Medicine, State Key Laboratory of Cardiovascular Disease, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
Weihua
W
Song
Department of Thoracic Surgery, Shanxi Dayi Hospital, Taiyuan, China.
Yuxuan
Y
Wang
Sino-German Laboratory for Molecular Medicine, State Key Laboratory of Cardiovascular Disease, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
Yu
Y
Chen
Sino-German Laboratory for Molecular Medicine, State Key Laboratory of Cardiovascular Disease, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
Yu
Y
Nie
Department of Cardiovascular Surgery, China-Japan Friendship Hospital, Beijing, China.
Zhidong
Z
Ye
Sino-German Laboratory for Molecular Medicine, State Key Laboratory of Cardiovascular Disease, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
Rutai
R
Hui
D020413:3' Untranslated Regions; D000368:Aged; D000818:Animals; D044466:Asian People / Q000235:genetics; D001665:Binding Sites; D016022:Case-Control Studies; D002478:Cells, Cultured; D000075222:Essential Hypertension; D005260:Female; D005786:Gene Expression Regulation; D020022:Genetic Predisposition to Disease; D006801:Humans; D006973:Hypertension / Q000150:complications / Q000235:genetics*; D017379:Hypertrophy, Left Ventricular / Q000209:etiology* / Q000235:genetics; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics* / Q000378:metabolism; D008297:Male; D035683:MicroRNAs / Q000378:metabolism*; D008875:Middle Aged; D032383:Myocytes, Cardiac / Q000166:cytology; D020641:Polymorphism, Single Nucleotide; D051381:Rats
D020413:3' Untranslated Regions; D036341:Intercellular Signaling Peptides and Proteins; D035683:MicroRNAs; C487931:mirnlet7 microRNA, human; C065700:myotrophin