The PGC-1α/NRF1/miR-378a axis protects vascular smooth muscle cells from FFA-induced proliferation, migration and inflammation in atherosclerosis

Background and aims: Atherosclerosis (AS) is the leading cause of cardiovascular diseases. PGC-1 alpha is a key regulator of cellular energy homeostasis, but its role in AS remains debatable. Methods and results: In our study, PGC-1 alpha was shown to be significantly decreased in the media of human atherosclerotic vessels. To explore whether miRNAs might be regulated by PGC-1 alpha in vascular smooth muscle cells (VSMCs), microarray analysis was performed. Microarray and Pearson's correlation analysis showed that PGC-1 alpha and miR-378a were positively correlated in vivo and in vitro. As an upstream co-activator, PGC-1 alpha was found to regulate miR-378a through binding to the transcriptional factor NRF1 in VSMCs. Therefore, the decreased expression of PGC-1 alpha might account for suppression of miR-378a in VSMCs in AS. Furthermore, IGF1 and TLR8, two genes known to be aberrantly up-regulated in atherogenic vessels, were identified as direct targets of miR-378a. In vitro up-regulation of miR-378a markedly inhibited free fatty acid (FFA)-induced VSMC proliferation, migration and inflammation through targeting IGF1 and TLR8. Conclusions: These findings highlight the protective role of the PGC-1 alpha/NRF1/miR-378a regulatory axis in AS progression and suggest miR-378a as potential therapeutic target for AS treatment.