Inhibition of DNA methyltransferase-1 instigates the expression of DNA methyltransferase-3a in angioplasty-induced restenosis

Abstract

Increased expression of DNA methyltransferase-1 (DNMT1) associates with the progression of many human diseases. Because DNMT1 induces cell proliferation, drugs that inhibit DNMT1 have been used to treat proliferative diseases. Because these drugs are nonspecific inhibitors of DNMT1, subsidiary events or the compensatory mechanisms that are activated in the absence of DNMT1 limit their therapeutic application. Here, we studied the molecular mechanisms that occur during angioplasty-induced restenosis and found that DNMT1 inhibition in both in vitro and in vivo approaches resulted in the induction of DNA methyltransferase-3a (DNMT3a) expression. In vascular smooth muscle cells (VSMCs), the microRNA hsa-miR-1264 mimic, specifically inhibiting DNMT1, induced nuclear expression of DNMT3a. On the contrary, there was no induced expression of DNMT3a in VSMCs that were transfected with hsa-miR-1264 inhibitor. Further, ectopic expression of suppressor of cytokine signaling 3 (SOCS3) through adeno-associated virus (AAV)-mediated gene delivery in the coronary arteries of Yucatan microswine showed inhibition of both DNMT1 and DNMT3a in vivo. These findings show the existence of an inter-regulatory mechanism between DNMT1 and DNMT3a where, in the absence of DNMT1, induction of DNMT3a compensates for the loss of DNMT1 functions, suggesting that the inhibition of both DNMT1 and DNMT3a are required to prevent restenosis.

circRNA‑0006896‑miR1264‑DNMT1 axis plays an important role in carotid plaque destabilization by regulating the behavior of endothelial cells in atherosclerosis

“…DNMT1 is an important enzyme implicated in DNA methylation, particularly in the promoter region of SOCS3. Moreover, CpG islands, one of which is located at kb 4.261-6.673 in the SOCS3 genomic locus, regulate DNMT1 function (27,28). miR-1264 downregulation facilitates persistent DNMT1 expression, thereby inducing SOCS3 promoter methylation and impacting its gene expression (27).…”

“…The circRNA-0006896 network in UA exosomes increases the proliferation and migration of HUVECs. Previous studies have documented that DNMT1 is a critical regulator of JNK, STAT, and NF-κB signaling during the development of UA because an increase DNMT1 expression results in CpG island hypermethylation in the promoter region of SOCS3, which downregulates its expression (28). Low expression of SOCS3 promotes JNK/STAT signaling, thus increasing the proliferation and migration of HUVECs (29), which in turn leads to plaque destabilization and promotes AS development (23,30,31).…”

“…4A). A previous report indicated that miR-1264 targets the DNMT1 transcript by binding to its 3'UTR, thus affecting DNMT1 expression and enzyme activity in miR-1264-transfected cells (27,28). Thus, it was hypothesized that circRNA-0006896 may regulate HUVEC behavior through a circRNA-0006896-miR-1264-DNMT1 axis.…”

Short communication: TNF-α and IGF-1 regulates epigenetic mechanisms of HDAC2 and HDAC10

“…Our previous studies have identified two different molecular pathways of DNMT1 that work independently to repress the expression of a tumor suppressor protein, SOCS3, and promotes the development of neointimal hyperplasia [ 1 , 22 – 24 ]. Our continued research in this direction led us to explore interacting proteins and pathways which regulate DNMT1 activity during restenosis.…”

“…Our continued research in this direction led us to explore interacting proteins and pathways which regulate DNMT1 activity during restenosis. Further, we also reported that when DNMT1 expression was inhibited in VSMCs, its absence was supplemented by another isoform of DNMT, DNMT3a [ 24 ]. Since DNA methylation is a key mechanism by which gene expression is regulated in a controlled manner, the induction of subsidiary methylases, in absence of DNMT1, seems to be required for cell survival.…”