N6-methyladenosine demethylase fat mass and obesity-associated protein suppresses hyperglycemia-induced endothelial cell injury by inhibiting reactive oxygen species formation via autophagy promotion.
J Diabetes Complications
; 38(8): 108801, 2024 Aug.
Article
en En
| MEDLINE
| ID: mdl-38935979
ABSTRACT
INTRODUCTION:
Hyperglycemia-induced endothelial cell injury is one of the main causes of diabetic vasculopathy. Fat mass and obesity-associated protein (FTO) was the first RNA N6-methyladenosine (m6A) demethylase identified; it participates in the pathogenesis of diabetes. However, the role of FTO in hyperglycemia-induced vascular endothelial cell injury remains unclear. MATERIALS ANDMETHODS:
The effects of FTO on cellular m6A, autophagy, oxidative stress, proliferation, and cytotoxicity were explored in human umbilical vein endothelial cells (HUVECs) treated with high glucose (33.3 mmol/mL) after overexpression or pharmacological inhibition of FTO. MeRIP-qPCR and RNA stability assays were used to explore the molecular mechanisms by which FTO regulates autophagy.RESULTS:
High glucose treatment increased m6A levels and reduced FTO protein expression in HUVECs. Wild-type overexpression of FTO markedly inhibited reactive oxygen species generation by promoting autophagy, increasing endothelial cell proliferation, and decreasing the cytotoxicity of high glucose concentrations. The pharmacological inhibition of FTO showed the opposite results. Mechanistically, we identified Unc-51-like kinase 1 (ULK1), a gene responsible for autophagosome formation, as a downstream target of FTO-mediated m6A modification. FTO overexpression demethylated ULK1 mRNA and inhibited its degradation in an m6A-YTHDF2-dependent manner, leading to autophagy activation.CONCLUSIONS:
Our study demonstrates the functional importance of FTO-mediated m6A modification in alleviating endothelial cell injury under high glucose conditions and indicates that FTO may be a novel therapeutic target for diabetic vascular complications.Palabras clave
Texto completo:
1
Base de datos:
MEDLINE
Asunto principal:
Autofagia
/
Especies Reactivas de Oxígeno
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Dioxigenasa FTO Dependiente de Alfa-Cetoglutarato
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Homólogo de la Proteína 1 Relacionada con la Autofagia
/
Hiperglucemia
Límite:
Humans
Idioma:
En
Revista:
J Diabetes Complications
/
J. diabetes its complicat
/
Journal of diabetes and its complications
Asunto de la revista:
ENDOCRINOLOGIA
Año:
2024
Tipo del documento:
Article
País de afiliación:
China