Overexpression of miR-1 in the heart attenuates hippocampal synaptic vesicle exocytosis by the posttranscriptional regulation of SNAP-25 through the transportation of exosomes

作者：Ming-Jing Duan, Meiling Yan, Qin Wang, Meng Mao, Dan Su, Linlin Sun, Kexin Li, Yang Qu, Qiang Sun, Xinyu Zhang, Siyu Huang, Jichao Ma, Tao Ban, Jing Ai · 发表于：Cell Communication and Signaling · 年份：2018 · DOI：10.1186/s12964-018-0303-5 · 被引用次数：36 · 研究领域：Extracellular vesicles in disease、Neurogenesis and neuroplasticity mechanisms、MicroRNA in disease regulation

BACKGROUND: The link between cardiac diseases and cognitive deterioration has been accepted from the concept of "cardiogenic dementia", which was proposed in the late 1970s. However, the molecular mechanism is unclarified. METHODS: The two animal models used in this study were cardiac-specific overexpression of microRNA-1-2 transgenic (Tg) mice and a myocardial infarction mouse model generated by left coronary artery ligation (LCA). First, we observed the microRNA-1 (miR-1) level and synaptic vesicles (SV) distribution in the hippocampus using in situ hybridization and transmission electron microscopy (TEM) and evaluated the expression of vesicle exocytosis related proteins by western blotting. Second, we used dual luciferase reporter assay as well as antagonist and miRNA-masking techniques to identify the posttranscriptional regulatory effect of miR-1 on the Snap25 gene. Third, FM1-43 staining was performed to investigate the effect of miR-1 on synaptic vesicle exocytosis. Lastly, we used GW4869 to inhibit the biogenesis and secretion of exosomes to determine the transportation effect of exosomes for miR-1 from the heart to the brain. RESULTS: Compared with the levels in age-matched WT mice, miR-1 levels were increased in both the hearts and hippocampi of Tg mice, accompanied by the redistribution of SVs and the reduction in SV exocytosis-related protein SNAP-25 expression. In vitro studies showed that SNAP-25 protein expression was down- or upregulated by miR-1 overexpressi...