Adenosine kinase is critical for neointima formation after vascular injury by inducing aberrant DNA hypermethylation.
Cardiovasc Res
; 117(2): 561-575, 2021 01 21.
Article
en En
| MEDLINE
| ID: mdl-32065618
ABSTRACT
AIMS:
Adenosine receptors and extracellular adenosine have been demonstrated to modulate vascular smooth muscle cell (VSMC) proliferation and neointima formation. Adenosine kinase (ADK) is a major enzyme regulating intracellular adenosine levels but is function in VSMC remains unclear. Here, we investigated the role of ADK in vascular injury-induced smooth muscle proliferation and delineated the mechanisms underlying its action. METHODS ANDRESULTS:
We found that ADK expression was higher in the neointima of injured vessels and in platelet-derived growth factor-treated VSMCs. Genetic and pharmacological inhibition of ADK was enough to attenuate arterial injury-induced neointima formation due to inhibition of VSMC proliferation. Mechanistically, using infinium methylation assays and bisulfite sequencing, we showed that ADK metabolized the intracellular adenosine and potentiated the transmethylation pathway, then induced the aberrant DNA hypermethylation. Pharmacological inhibition of aberrant DNA hypermethylation increased KLF4 expression and suppressed VSMC proliferation as well as the neointima formation. Importantly, in human femoral arteries, we observed increased ADK expression and DNA hypermethylation as well as decreased KLF4 expression in neointimal VSMCs of stenotic vessels suggesting that our findings in mice are relevant for human disease and may hold translational significance.CONCLUSION:
Our study unravels a novel mechanism by which ADK promotes VSMC proliferation via inducing aberrant DNA hypermethylation, thereby down-regulating KLF4 expression and promoting neointima formation. These findings advance the possibility of targeting ADK as an epigenetic modulator to combat vascular injury.Palabras clave
Texto completo:
1
Bases de datos:
MEDLINE
Asunto principal:
Adenosina Quinasa
/
Metilación de ADN
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Traumatismos de las Arterias Carótidas
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Miocitos del Músculo Liso
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Epigénesis Genética
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Proliferación Celular
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Neointima
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Músculo Liso Vascular
Tipo de estudio:
Prognostic_studies
Límite:
Animals
/
Humans
Idioma:
En
Revista:
Cardiovasc Res
Año:
2021
Tipo del documento:
Article
País de afiliación:
China