MicroRNA-19b/221/222 induces endothelial cell dysfunction via suppression of PGC-1α in the progression of atherosclerosis.

Abstract

Peroxisome proliferator-activated receptor γ coactivator 1α (PGC-1α) is a master regulator of cellular energy metabolism that is associated with many cardiovascular diseases, including atherosclerosis. However, the role and underling regulatory mechanisms of PGC-1α in the pathogenesis of atherosclerosis are not completely understood. Here, we identified the microRNAs that post-transcriptionally regulate PGC-1α production and their roles in the pathogenesis of atherosclerosis. A significant down-regulation of PGC-1α protein was observed in human atherosclerotic vessel samples. Using microarray and bioinformatics analyses, PGC-1α was identified as a common target gene of miR-19b-3p, miR-221-3p and miR-222-3p, which are mainly located in the intima of atherosclerotic vessels. Invitro induction of miR-19b-3p, miR-221-3p and miR-222-3p by the inflammatory cytokines TNFα and IFNγ may affect PGC-1α protein production and consequently result in mitochondrial dysfunction in Human Aortic Endothelial Cells (HAECs). The overexpression of miR-19b-3p, miR-221-3p and miR-222-3p in HAECs caused intracellular ROS accumulation, which led to cellular apoptosis. Taken together, these results demonstrate that PGC-1α plays a protective role against the vascular complications of atherosclerosis. Moreover, the posttranscriptional regulation of PGC-1α by miR-19b/221/222 was unveiled, which provides a novel mechanism in which a panel of microRNAs can modulate endothelial cell apoptosis via the regulation mitochondrial function.