METTL3-mediated N6-methyladenosine modification contributes to vascular calcification

Area of Science:

• Biochemistry
• Molecular Biology
• Cardiovascular Research

Background:

• Vascular calcification (VC) is a significant cardiovascular complication in chronic kidney disease (CKD).
• The role and mechanisms of N6-methyladenosine (m6A) modification in VC remain largely unexplored.
• N6-adenosine-methyltransferase-like 3 (METTL3) is a key m6A writer enzyme.

Purpose of the Study:

• To elucidate the function of METTL3 in vascular calcification (VC).
• To investigate the underlying molecular mechanisms of METTL3 in VC pathogenesis.
• To identify potential therapeutic strategies targeting METTL3 for VC.

Main Methods:

• Bioinformatic analysis of METTL3 expression in calcified vascular smooth muscle cells (VSMCs).
• In vitro (VSMCs) and in vivo (CKD mouse models) experimental validation of METTL3's role in VC.
• Assessment of m6A levels, calcium deposition, and signaling pathways (PTEN/AKT).
• RNA immunoprecipitation (MeRIP) assay to confirm m6A modification of PTEN mRNA.
• Molecular docking and DARTS assays to identify quercetin as a METTL3 inhibitor.

Main Results:

• METTL3 expression was upregulated in calcified VSMCs and in VC models of CKD mice.
• METTL3 overexpression enhanced m6A levels and promoted calcification, while knockdown inhibited these effects.
• METTL3 promoted VC via the PTEN/AKT pathway by inducing PTEN mRNA degradation through m6A modification.
• Quercetin was identified as a natural inhibitor of METTL3, effectively mitigating VC in vitro and in vivo.

Conclusions:

• METTL3 plays a critical role in the pathogenesis of vascular calcification (VC) through m6A modification.
• The METTL3-mediated m6A modification of PTEN mRNA contributes to VC development.
• METTL3 represents a promising therapeutic target for managing VC in chronic kidney disease (CKD) patients.
• Quercetin demonstrates potential as a therapeutic agent for VC by inhibiting METTL3 activity.