The miR-143/145 cluster reverses the regulation effect of KLF5 in smooth muscle cells with proliferation and contractility in intracranial aneurysm.

Alterations in vascular smooth muscle cells (VSMCs) contribute to the pathogenesis of intracranial aneurysms (IAs), but the molecular mechanisms of these alterations are unclear. The aim of this study was therefore to identify the molecular mechanism of VSMC-mediated IAs at clinical and cellular levels. We used bioinformatic and biochemical analyses to show that the microRNA (miR)-143/145 cluster was involved in various biological processes related to aneurysm formation. Clinical studies showed that the miR-143/145 cluster was downregulated in IA patients when compared with healthy subjects. However, KLF5 expression was upregulated in IA patients. In vitro experiments showed that overexpression of the miR-143/145 cluster inhibited proliferation and migration of VSMCs, but increased contractile protein expression and decreased matrix metalloproteinase-2 and -3. KLF5 overexpression had the opposite effect, even reversing the protective effect of the miR-143/145 cluster on IAs. Bifluorescein report experiments further confirmed that both miR-143 and miR-145 interacted with the 3'-UTR of KLF5 and inhibited post-transcriptional expression of KLF5. Taken together, the results showed that VSMC phenotypic modulation with upregulation of KLF5 by downregulation of the miR-143/145 cluster played an important role in formation and growth of IAs. The process of IA formation was reversed by overexpression of the miR-143/145 cluster. Together, the results provided a theoretical basis for further investigation of the potential clinical prevention and treatment of IAs.