miR-146a and Krüppel-like factor 4 form a feedback loop to participate in vascular smooth muscle cell proliferation

MicroRNAs are phenotypic regulators of vascular smooth muscle cells (VSMCs). In this paper, we demonstrate that miR‐146a targets the Krüppel‐like factor 4 ( KLF4 ) 3′‐untranslated region and has an important role in promoting VSMC proliferation in vitro and vascular neointimal hyperplasia in vivo . Silencing of miR‐146a in VSMCs increases KLF4 expression, whereas overexpression of miR‐146a decreases KLF4 levels. Furthermore, we demonstrate that KLF4 competes with Krüppel‐like factor 5 (KLF5) to bind to and regulate the miR‐146a promoter, and that KLF4 and KLF5 exert opposing effects on the miR‐146a promoter. Overexpression of KLF4 in VSMCs decreases miR‐146a transcription levels. By using both gain‐of‐function and loss‐of‐function approaches, we found that miR‐146a promotes VSMC proliferation in vitro . Transfection of antisense miR‐146a oligonucleotide into balloon‐injured rat carotid arteries markedly decreased neointimal hyperplasia. These findings suggest that miR‐146a and KLF4 form a feedback loop to regulate each other's expression and VSMC proliferation. miR‐146a and KLF4 negatively regulate each other?s expression and miR‐146a thereby promotes vascular smooth muscle cell proliferation. Depletion of miR‐146a in injured rat carotid arteries decreases hyperplasia and this might have therapeutic implications for proliferative vascular diseases.