Histone methyltransferase G9a drives ferroptosis to aggravate vascular calcification by inhibiting SLC7A11 transcription

Area of Science:

• Cardiovascular Biology
• Epigenetics
• Renal Medicine

Background:

• Vascular calcification (VC) is a major risk factor for cardiovascular disease in chronic kidney disease (CKD).
• Ferroptosis, a regulated cell death pathway, is increasingly recognized for its role in VC pathogenesis.
• The histone methyltransferase G9a's role in VC and ferroptosis remains largely unexplored.

Purpose of the Study:

• To investigate the role and mechanism of G9a in vascular calcification associated with chronic kidney disease.
• To elucidate the involvement of ferroptosis in G9a-mediated VC.
• To identify potential therapeutic targets for VC in CKD.

Main Methods:

• Analysis of G9a expression in CKD patient and mouse vascular smooth muscle cells (VSMCs) and arterial tissues.
• In vitro experiments assessing the effects of G9a overexpression and deficiency on VSMC calcification.
• Investigation of the G9a/H3K9me2/SLC7A11 signaling axis and its impact on ferroptosis.
• In vivo studies using CKD mouse models to evaluate the effects of G9a on VC and ferroptosis.

Main Results:

• G9a expression is significantly elevated in VSMCs and arteries from CKD models and patients.
• G9a overexpression exacerbates high calcium and phosphate-induced VSMC calcification, while G9a deficiency is protective.
• G9a promotes VSMC calcification by inhibiting SLC7A11 transcription via H3K9me2, thereby mediating ferroptosis.
• In vivo, G9a overexpression aggravates VC and ferroptosis in CKD mouse aortas, with concurrent SLC7A11 downregulation.

Conclusions:

• The G9a/H3K9me2/SLC7A11 pathway represents a novel molecular mechanism driving ferroptosis in vascular calcification.
• Targeting G9a may provide a new therapeutic avenue for managing vascular calcification in patients with chronic kidney disease.