YTHDC2-Mediated circYTHDC2 N6-Methyladenosine Modification Promotes Vascular Smooth Muscle Cells Dysfunction Through...

Area of Science:

• Biochemistry
• Molecular Biology
• Cardiovascular Research

Background:

• Type 2 diabetes mellitus (T2DM) is associated with vascular smooth muscle cell (VSMC) dysfunction, contributing to diabetic vascular complications.
• The precise mechanisms underlying VSMC dysfunction in T2DM require further investigation.
• Circular RNAs (circRNAs) have emerged as critical regulators in the development of VSMC dysfunction.

Purpose of the Study:

• To elucidate the role of circRNAs in high glucose-induced VSMC dysfunction.
• To identify novel circRNAs involved in the pathogenesis of diabetic vascular complications.
• To investigate the therapeutic potential of targeting identified circRNAs with metformin.

Main Methods:

• Vascular smooth muscle cells (VSMCs) were stimulated with high glucose.
• CircRNA chip analysis was employed to identify differentially expressed circRNAs.
• circYTHDC2 was knocked out to assess its functional impact on VSMC proliferation and migration.
• Metformin treatment effects on YTHDC2 and circYTHDC2 expression were evaluated.
• Upstream mechanisms, including m6A modification and TET2 regulation, were analyzed.

Main Results:

• A novel circRNA, circYTHDC2, was identified and found to be highly expressed in high glucose-treated VSMCs.
• Knockout of circYTHDC2 significantly inhibited VSMC proliferation and migration.
• Metformin treatment markedly reduced the expression of YTHDC2 and circYTHDC2.
• circYTHDC2 stability is regulated by YTHDC2-mediated m6A modification.
• circYTHDC2 negatively regulates Ten-Eleven Translocation 2 (TET2) expression by targeting its 3'UTR, promoting VSMC dedifferentiation.

Conclusions:

• The YTHDC2/circYTHDC2/TET2 pathway plays a crucial role in high glucose-induced VSMC dysfunction.
• circYTHDC2 promotes VSMC dedifferentiation and transformation into a synthetic phenotype.
• Targeting the YTHDC2/circYTHDC2/TET2 pathway represents a potential therapeutic strategy for metformin in mitigating diabetic vascular complications.