Nullifying epigenetic writer DOT1L attenuates neointimal hyperplasia

Huang, Yitao; Urabe, Go; Zhang, Mengxue; Li, Jing; Özer, Hatice Gülçin; Wang, Bowen; Kent, K. Craig

doi:10.1016/j.atherosclerosis.2020.06.002

Cited by 13 publications

(3 citation statements)

References 26 publications

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“…Immediately following the surgery, scrambled or miR579-3p lentivirus were filled in the isolated common carotid artery for 25 min. This local delivery of lentivirus for gene transfer to the injured artery wall has proven effective in our previous reports [ 61 , 62 ], and the miR579-3p sequence was herein confirmed to be functionally effective for rat cells via miR579-3p transfection of cultured rat primary SMCs (Fig. S1 ).…”

Section: Methodssupporting

confidence: 63%

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

Xie

Shirasu

et al. 2023

Cell Death Discov.

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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.

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Section: Methodssupporting

confidence: 63%

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

Xie

Shirasu

et al. 2023

Cell Death Discov.

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“…For example, reduced acetylation of histone H4 was reported in PDGF-BB-stimulated VSMCs and in rat carotid artery after balloon injury [124]. Similarly, disruption of telomeric silencing 1-like (DOT1L), the only known methylation writer at histone 3 lysine 79 (H3K79), has been shown to contribute to VSMC proliferation and consequently intimal hyperplasia [130]. Evidence supporting this notion is provided by a study that looked into genome-wide DNA methylation changes in atherosclerotic aorta [131].…”

Section: Mechanisms Of Rhoa/rock-induced Vsmc Dedifferentiationmentioning

confidence: 99%

Role of RhoA and Rho-associated kinase in phenotypic switching of vascular smooth muscle cells: Implications for vascular function

et al. 2022

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“…Epigenetic writers oversee promoting the addition of active and suppressive tags to DNA or histones. Among the plethora of chemical groups that can be added to DNA and histone proteins by a variety of writer enzymes [97], the two most common epigenetic alterations are methylationthat occurs on both histone proteins and DNA and acetylation, which occurs solely on histones [98]. These two changes commonly influence cellular gene expression patterns by switching between transcriptional activation and suppression [99].…”

Section: Epigenetic Writersmentioning

confidence: 99%