The feedback regulation of PI3K-miR-19a, and MAPK-miR-23b/27b in endothelial cells under shear stress.

Mechanical stimulation regulates endothelial cell (EC) functions through the modulation of signaling networks and gene expression. Our recent studies have identified that shear stress regulation of microRNAs (miRs)-19a, 23b and 27b, led to the modulation of EC proliferation. However, the underlying molecular mechanisms by which shear stress regulates these miRs have not been explored. Previous studies showed that shear stress activates multiple signaling pathways, including phosphatidylinositol 3 kinase (PI3K) and mitogen-activated protein kinase (MAPK). In this work we demonstrate that inhibition of the PI3K pathway attenuated the shear-induced miR-19a, and inhibition of the MAPK pathway attenuated miR-23b, 27b. The knockdown of miR-19a using antagomir-19a oligonucleotide (AM19a) decreased the shear-induced PI3K activation; whereas AM-23b, 27b reduced the shear-induced MAPK activation. Furthermore, the overexpression of miR-19a overrode the suppressive effects of PI3K inhibitors on shear-induced PI3K activation; the overexpression of miR-23b, 27b had similar effects on ERK activations, but had little effect on P38 and JNK activation. Our findings suggest a positive feedback loop whereby PI3K and MAPK mediate the shear regulation of miR expression, which in turn modulates the shear-regulated PI3K/MAPK signaling events in ECs.