ATF3 Deficiency Exacerbates Ageing-Induced Atherosclerosis and Clinical Intervention Strategy

Area of Science:

• Cardiovascular Biology
• Molecular Aging
• Cellular Senescence

Background:

• Vascular smooth muscle cell (VSMC) senescence drives atherosclerosis (AS), but its molecular regulation in aging is poorly understood.
• Identifying key regulators of VSMC senescence is crucial for developing interventions against age-related cardiovascular disease.

Purpose of the Study:

• To identify novel regulators of VSMC senescence and explore therapeutic strategies for age-related AS.
• To elucidate the molecular mechanisms by which activating transcription factor 3 (ATF3) influences VSMC senescence and AS.

Main Methods:

• Single-cell RNA sequencing of human carotid arteries, immunofluorescence, and in vivo studies using SMC-specific ATF3 knockout mice.
• CUT&Tag-seq, RNA-protein interaction assays, m6A epitranscriptomic analysis, and high-throughput virtual screening for ATF3-targeting compounds.
• Functional validation of identified compounds and mechanistic studies on the ATF3-ATG7 feedback loop and m6A modification of Atf3 mRNA.

Main Results:

• ATF3 was identified as a central regulator of VSMC senescence, with ATF3 deficiency accelerating aging-induced AS.
• A novel positive feedback loop was discovered where ATF3 activates ATG7, promoting autophagy, and cytoplasmic ATG7 enhances ATF3 nuclear translocation.
• Age-related m6A methylation destabilizes Atf3 mRNA; terazosin (TZ) was found to stabilize Atf3 mRNA by inhibiting YTHDF2 interaction, thereby preserving ATF3 levels.

Conclusions:

• ATF3 protects against VSMC senescence and AS by orchestrating autophagy through an ATF3-ATG7 amplification loop.
• Stabilizing ATF3 via repurposing terazosin presents a translatable therapeutic approach to mitigate aging-driven cardiovascular disease.
• The findings provide critical insights into the molecular mechanisms of VSMC senescence and offer a potential strategy for treating age-related atherosclerosis.