Glut1-dependent lactylation drives VSMC senescence phenotype

Area of Science:

• Cardiovascular Research
• Cellular Senescence
• Metabolic Pathways

Background:

• Atherosclerosis (AS) is a major cause of cardiovascular and cerebrovascular diseases.
• Vascular smooth muscle cell (VSMC) senescence is a key driver of AS, but its molecular mechanisms are not fully understood.
• Identifying novel therapeutic targets for AS requires deeper insight into VSMC aging.

Purpose of the Study:

• To investigate the role of glucose transporter 1 (Glut1) in VSMC senescence during atherosclerosis.
• To elucidate the molecular mechanisms linking Glut1 to VSMC aging.
• To explore potential therapeutic targets based on the Glut1-mediated pathway.

Main Methods:

• Studied Glut1 expression in mouse aortic VSMCs (MOVAS) during AS progression.
• Utilized in vitro experiments involving Glut1 knockdown and overexpression in MOVAS.
• Investigated the glycolysis-lactate-H3K18la signaling axis and its components (P300, HDAC-1).

Main Results:

• Glut1 was upregulated in MOVAS during AS, correlating with aging markers (P16, P21) and senescence-associated secretory phenotype (SASP) factors.
• Glut1 knockdown inhibited VSMC aging, while overexpression exacerbated it.
• The Glut1-lactate-H3K18la pathway was identified as a key mechanism promoting MOVAS aging.

Conclusions:

• Establishes a mechanistic link between Glut1, lactate, and H3K18 lactylation in driving VSMC premature aging.
• Highlights the Glut1-lactate-H3K18la axis as a critical metabolic-epigenetic pathway in AS pathogenesis.
• Provides a theoretical basis for developing targeted therapies against VSMC senescence in atherosclerosis.