MicroRNA-19B/221/222 Induces Endothelial Cell Dysfunction Via Suppression Of PGC1α In The Progression Of Atherosclerosis

Peroxisome proliferator-activated receptory coactivator (PGC)-1α is a member of a family of transcription coactivators, the expression of which is most abundant in tissues that have a demand for energy production. These tissues include BAT, heart, skeletal muscle, kidney and brain. PGC1α has a close connection with energy metabolism and plays a central role in the regulation of physical and pathological activities through the cooperating with a series of transcription factors, for example atherosclerosis, muscle dysfunction and diabetes. However, the underlying mechanism of PGC1α in the progression of atherosclerosis is not completely understood.Our previous studies demonstrated that PGCla could inhibit the proliferation and migration of rat VSMC (vascular smooth muscle cell, VSMC) in pathological conditions. Overexpression PGCla in VSMC could inhibit the proliferation and migration induced by high fat, high glucose or PDGF-BB, and VSMC treated with dexamethasone also shows the low proliferation and migration ratio, showing that PGC1α possesses the ability of anti-atherosclerotic. In this study, compared with the normal vessel, a significant down-regulation of PGCla protein was observed in human atherosclerotic vessel samples, but its mRNA was upregulated dramatically, showing that there is a post-transcriptional regulation controlling the PGCla expression. Using microarray and bioinformatics analyses, miR-19b/221/222 derived from the endothelium is predicted to combine with the 3’UTR of PGC1α, thus inhibiting the PGC1α expression. Meanwhile, TNFa and INFy were used to stimulate HAEC used in simulations of phenomena, the infiltration of inflammatory cytokines, in the progression of AS. The results showed that, with the extension of treated time, expression of miR-19b/221/222 increased gradually, while the PGCla proteins level was down-regulated. Abnormal rising of miR-19b/221/222 also affect the PGCla related functions, for example, mitochondrion numbers, ROS production and cell apotosis.The findings above suggests that the abnormal expression of miR-19b/221/222 could impair the PGCla expression, and then contribute to the endothelial dysfunction, Overexpression of miR-19b/221/222 could regulate the PGCla at the posttranscriptional levels, and thus inhibit the PGC1α protein production. And also, functions of PGCla were affected, including mitochondria biogenesis, ROS production and cell apoptosis. Our study revealed the posttranscriptional regulation mechanism of PGC-la via miR-19b/221/222, providing the new perspective for the diagnosis and treatment of atherosclerosis.