A Single-Nucleotide Polymorphism in 3’-Untranslated Region of Endothelin-1 Reduces Risk of Dementia After Ischemic Stroke
Wanwan Ma, Qizhi Fu, Yanpeng Zhang, Zhen Zhang
(Department of Neurology, The First Affiliated Hospital of Henan University of Science and Technology, Luoyang, Henan, China (mainland))
Med Sci Monit 2016; 22:1368-1374
Ischemic stroke is widely recognized as a major health problem and social burden worldwide, and it usually leads to dementia. In this study, we aimed to better understand the pathogenesis in the development of dementia following ischemic stroke.
MATERIAL AND METHODS: We exploited miRNA database to search for the target for miR-125a and validated the found target using luciferase assay. Further, we performed real-time PCR and Western blot analysis to examine the expression of miR-125a and its target in the tissue samples. In addition, a polymorphism was genotyped and its association with post-stroke dementia was analyzed.
RESULTS: We identified enthothelin-1 (ET-1) as a target of miR-125a, and this relationship was validated using luciferase assay. Furthermore, transfection of miR-125a inhibitor substantially upregulated the expression of ET-1, while miR-125a and ET-1 siRNA caused downregulation of ET-1 in endothelial cells. In addition, we found that a polymorphism (rs12976445) interferes with the expression of miR-125a, which in turn caused an increase in the expression of ET-1 in human endothelial cells. Logistic regression analysis showed that rs12976445 is significantly associated with the risk of dementia after ischemic stroke.
CONCLUSIONS: Our study demonstrated the pathogenesis mechanism during the development of dementia after ischemic stroke by investigating the relationship between miR-125a and its target ET-1, promising a potential pathological solution for post-stroke dementia in the future.
Keywords: 3' Untranslated Regions - genetics, Base Sequence, Brain Ischemia - complications, Case-Control Studies, Dementia - genetics, Demography, Endothelin-1 - metabolism, Gene Expression Regulation, Genetic Predisposition to Disease, Human Umbilical Vein Endothelial Cells - metabolism, Humans, Luciferases - metabolism, MicroRNAs - genetics, Polymorphism, Single Nucleotide - genetics, RNA, Messenger - metabolism, Stroke - complications, Transfection