miR579-3p is an inhibitory modulator of neointimal hyperplasia and transcription factors c-MYB and KLF4

Xiujie Xie; Takuro Shirasu; Jing Li; Lian-Wang Guo; K Craig Kent

doi:10.1038/s41420-023-01364-7

miR579-3p is an inhibitory modulator of neointimal hyperplasia and transcription factors c-MYB and KLF4

Cell Death Discov. 2023 Feb 22;9(1):73. doi: 10.1038/s41420-023-01364-7.

Authors

Xiujie Xie¹, Takuro Shirasu², Jing Li², Lian-Wang Guo^{3

4

5}, K Craig Kent⁶

Affiliations

¹ Department of Surgery, School of Medicine, University of Virginia, Charlottesville, VA, 22908, USA. [email protected].
² Department of Surgery, School of Medicine, University of Virginia, Charlottesville, VA, 22908, USA.
³ Department of Surgery, School of Medicine, University of Virginia, Charlottesville, VA, 22908, USA. [email protected].
⁴ Department of Molecular Physiology and Biological Physics, University of Virginia, Charlottesville, VA, 22908, USA. [email protected].
⁵ Robert M. Berne Cardiovascular Research Center, University of Virginia, Charlottesville, VA, 22908, USA. [email protected].
⁶ Department of Surgery, School of Medicine, University of Virginia, Charlottesville, VA, 22908, USA. [email protected].

Abstract

Neointimal hyperplasia (IH) is a common vascular pathology that typically manifests in in-stent restenosis and bypass vein graft failure. Smooth muscle cell (SMC) phenotypic switching is central to IH, both regulated by some microRNAs, yet the role of miR579-3p, a scarcely studied microRNA, is not known. Unbiased bioinformatic analysis suggested that miR579-3p was repressed in human primary SMCs treated with different pro-IH cytokines. Moreover, miR579-3p was software-predicted to target both c-MYB and KLF4 - two master transcription factors known to promote SMC phenotypic switching. Interestingly, treating injured rat carotid arteries via local infusion of miR579-3p-expressing lentivirus reduced IH 14 days after injury. In cultured human SMCs, transfection with miR579-3p inhibited SMC phenotypic switching, as indicated by decreased proliferation/migration and increased SMC contractile proteins. miR579-3p transfection downregulated c-MYB and KLF4, and luciferase assays indicated miR579-3p's targeting of the 3'UTRs of the c-MYB and KLF4 mRNAs. In vivo, immunohistochemistry showed that treatment of injured rat arteries with the miR579-3p lentivirus reduced c-MYB and KLF4 and increased SMC contractile proteins. Thus, this study identifies miR579-3p as a previously unrecognized small-RNA inhibitor of IH and SMC phenotypic switch involving its targeting of c-MYB and KLF4. Further studies on miR579-3p may provide an opportunity for translation to develop IH-mitigating new therapeutics.

Abstract

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