Abstract
Neointimal hyperplasia is a major clinical complication of coronary artery bypass
graft and percutaneous coronary intervention. Smooth muscle cells (SMCs) play a vital
roles in neointimal hyperplasia development and undergo complex phenotype switching.
Previous studies have linked glucose transporter member 10(Glut10) to the phenotypic
transformation of SMCs. In this research, we reported that Glut10 helps maintain the
contractile phenotype of SMCs. The Glut10-TET2/3 signaling axis can arrest neointimal
hyperplasia progression by improving mitochondrial function via promotion of mtDNA
demethylation in SMCs. Glut10 is significantly downregulated in both human and mouse
restenotic arteries. Global Glut10 deletion or SMC-specific Glut10 ablation in the
carotid artery of mice accelerated neointimal hyperplasia, while Glut10 overexpression
in the carotid artery triggered the opposite effects. All of these changes were accompanied
by a significant increase in vascular SMCs migration and proliferation. Mechanistically,
Glut10 is expressed primarily in the mitochondria after platelet-derived growth factor-BB
(PDGF-BB) treatment. Glut10 ablation induced a reduction in ascorbic acid (VitC) concentrations
in mitochondria and mitochondrial DNA (mtDNA) hypermethylation by decreasing the activity
and expression of the Ten-eleven translocation (TET) protein family. We also observed
that Glut10 deficiency aggravated mitochondrial dysfunction and decreased the adenosinetriphosphate
(ATP) content and the oxygen consumption rate, which also caused SMCs to switch their
phenotype from contractile to synthetic phenotype. Furthermore, mitochondria-specific
TET family inhibition partially reversed these effects. These results suggested that
Glut10 helps maintain the contractile phenotype of SMCs. The Glut10-TET2/3 signaling
axis can arrest neointimal hyperplasia progression by improving mitochondrial function
via the promotion of mtDNA demethylation in SMCs.
Keywords
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Article info
Publication history
Published online: May 21, 2023
Accepted:
May 9,
2023
Received in revised form:
May 7,
2023
Received:
October 9,
2022
Publication stage
In Press Journal Pre-ProofIdentification
Copyright
© 2023 Elsevier Inc. All rights reserved.
