MicroRNA-23b prevents aortic aneurysm formation by inhibiting smooth muscle cell phenotypic switching via FoxO4 suppression

Phenotypic switching of vascular smooth muscle cells (VSMCs) is essential for the formation of abdominal aortic aneurysms (AAAs). MicroRNA-23b (miR-23b) has recently been shown to play a vital role in maintaining the VSMC contractile phenotype; however, little is known about the role of miR-23b in the formation of AAAs. Here, we investigated whether miR-23b prevents AAA formation by inhibiting VSMC phenotypic switching. We administered angiotensin II (Ang II, 1000 ng/kg/min) or vehicle to 10–12-week-old male apolipoprotein E knockout (ApoE−/−) or C57BL/6J mice via subcutaneous osmotic minipumps for 4 weeks. The expression of miR-23b was significantly reduced in the aorta during the early onset of AAA in angiotensin II-treated ApoE−/− mice and in human AAA samples. In vitro experiments showed that the suppression of SMC contractile marker gene expression induced by Ang II was accelerated by miR-23b inhibitors but inhibited by mimics. In vivo studies revealed that miR-23b deficiency in Ang II-treated C57BL/6J mice aggravated the formation of AAAs in these mice compared with control mice; the opposite results were observed in miR-23b-overexpressing mice. Mechanistically, miR-23b knockdown significantly increased the expression of the transcription factor forkhead box O4 (FoxO4) during VSMC phenotypic switching induced by Ang II. In addition, a luciferase reporter assay showed that FoxO4 is a target of miR-23b in VSMCs. Our study revealed a pivotal role for miR-23b in protecting against aortic aneurysm formation by maintaining the VSMC contractile phenotype. •Little is known about the role of miR-23b in the formation of AAAs.•In vivo studies revealed that miR-23b overexpressing in angiotensin II-treated mice inhibited the formation of AAAs.•Therapeutic approaches designed to increase miR-23b expression will be beneficial for preventing AAAs formation.