Detailed Information

Cited 3 time in webofscience Cited 10 time in scopus
Metadata Downloads

FAK Activation Promotes SMC Dedifferentiation via Increased DNA Methylation in Contractile Genesopen access

Authors
Jeong, KyuhoMurphy, James M.Kim, Jung-HyunCampbell, Pamela MoorePark, HyeonsooRodriguez, YelitzaChoi, ChungsikKim, Jun-SubPark, SangwonKim, Hyun JoonScammell, Jonathan G.Weber, David S.Honkanen, Richard E.Schlaepfer, David D.Ahn, Eun-Young ErinLim, Ssang-Taek Steve
Issue Date
3-Dec-2021
Publisher
LIPPINCOTT WILLIAMS & WILKINS
Keywords
atherosclerosis; DNA methylation; focal adhesion protein-tyrosine kinases; methyltransferases; neointima; vascular remodeling
Citation
CIRCULATION RESEARCH, v.129, no.12, pp.E215 - E233
Indexed
SCIE
SCOPUS
Journal Title
CIRCULATION RESEARCH
Volume
129
Number
12
Start Page
E215
End Page
E233
URI
https://scholarworks.bwise.kr/gnu/handle/sw.gnu/2870
DOI
10.1161/CIRCRESAHA.121.319066
ISSN
0009-7330
Abstract
Rationale: Vascular smooth muscle cells (SMCs) exhibit remarkable plasticity and can undergo dedifferentiation upon pathological stimuli associated with disease and interventions. Objective: Although epigenetic changes are critical in SMC phenotype switching, a fundamental regulator that governs the epigenetic machineries regulating the fate of SMC phenotype has not been elucidated. Methods and Results: Using SMCs, mouse models, and human atherosclerosis specimens, we found that FAK (focal adhesion kinase) activation elicits SMC dedifferentiation by stabilizing DNMT3A (DNA methyltransferase 3A). FAK in SMCs is activated in the cytoplasm upon serum stimulation in vitro or vessel injury and active FAK prevents DNMT3A from nuclear FAK-mediated degradation. However, pharmacological or genetic FAK catalytic inhibition forced FAK nuclear localization, which reduced DNMT3A protein via enhanced ubiquitination and proteasomal degradation. Reduced DNMT3A protein led to DNA hypomethylation in contractile gene promoters, which increased SMC contractile protein expression. RNA-sequencing identified SMC contractile genes as a foremost upregulated group by FAK inhibition from injured femoral artery samples compared with vehicle group. DNMT3A knockdown in injured arteries reduced DNA methylation and enhanced contractile gene expression supports the notion that nuclear FAK-mediated DNMT3A degradation via E3 ligase TRAF6 (TNF [tumor necrosis factor] receptor-associated factor 6) drives differentiation of SMCs. Furthermore, we observed that SMCs of human atherosclerotic lesions exhibited decreased nuclear FAK, which was associated with increased DNMT3A levels and decreased contractile gene expression. Conclusions: This study reveals that nuclear FAK induced by FAK catalytic inhibition specifically suppresses DNMT3A expression in injured vessels resulting in maintaining SMC differentiation by promoting the contractile gene expression. Thus, FAK inhibitors may provide a new treatment option to block SMC phenotypic switching during vascular remodeling and atherosclerosis.
Files in This Item
There are no files associated with this item.
Appears in
Collections
College of Medicine > Department of Medicine > Journal Articles

qrcode

Items in ScholarWorks are protected by copyright, with all rights reserved, unless otherwise indicated.

Related Researcher

Researcher Kim, Hyun Joon photo

Kim, Hyun Joon
의과대학 (의학과)
Read more

Altmetrics

Total Views & Downloads

BROWSE