ATF4 promotes brain vascular smooth muscle cells proliferation, invasion and migration by targeting miR-552-SKI axis

Abstract

Background Studies have indicated vascular smooth muscle cells (VSMCs) played a crucial role in atherosclerosis and microRNAs (miRNAs) played key roles in biological functions of VSMCs. Whereas, the potential function and mechanism of miR-552 in VSMCs remains unclear. Our aim was to explore the role of miR-552 on VSMCs and underlying mechanism. Material/Methods MTT assay and transwell assay were used to measure the proliferation, invasion, and migration of human brain VSMCs (HBVSMCs) and mice VSMCs (mVSMCs), respectively. Bioinformatics tools and luciferase assay were adopted to verify the association between miR-552 and SKI. Rescue experiments were employed to assess the interaction of miR-552 and SKI in modulating biological functions in HBVSMCs and mVSMCs. The expression level of transcription factors (TFs)was measured via qRT-PCR assay. The effect of ATF4 on miR-552 and SKI expression was tested by qRT-PCR or western blot assay. Finally, chromatin immunoprecipitation (ChIP) assay and JASPAR databases were used to analyze the regulatory linkage between ATF4 and miR-552. Results We found that miR-552 was upregulated in HBVSMCs treated with PDGF-bb and miR-552 overexpression could promote proliferation, invasion, and migration of HBVSMCs and mVSMCs, whereas, miR-552 knockdown had the opposite impact. In addition, we also found that SKI was a direct target of miR-552, which reversed miR-552-mediated proliferation, invasion, and migration in HBVSMCs and mVSMCs. Furthermore, we also discovered that miR-552 overexpression promoted the effects of ATF4 elevation on proliferation, migration and invasion of HBVSMCs and mVSMCs, but, miR-552 decline had the opposite impact. Conclusions ATF4-miR-552-SKI axis played critical roles in the proliferation and migration of HBVSMCs and mVSMCs, which were closely involved in atherosclerosis (AS). Therefore, our findings might offer a novel therapeutic target for AS.

Role of MicroRNAs and Retroelements in the Pathogenesis of Atherosclerosis

“…MiR-548 регулирует экспрессию HMGB1 (негистоновый белок, связывающий хроматин и участвующий в контроле транскрипции, репликации и репарации ДНК) [55]. В сосудах головного мозга больных АС экспрессия miR-552 (произошла от LINE1 [23]) повышается под влиянием PDGF-BB (фактор роста тромбоцитов-BB) в ГМКС, что ведет к стимуляции их пролиферации, инвазии и миграции [56].…”