Study Background and Disease Burden
Atherosclerosis is a prevalent age-associated vascular disease characterized by plaque formation within arterial walls, leading to vessel narrowing and compromised blood flow. Among the pathological hallmarks of atherosclerosis is the senescence of vascular smooth muscle cells (VSMCs), which accelerates pathological remodeling, increases vessel stiffness, and exacerbates cardiovascular risk. Despite advances in managing traditional risk factors such as hypertension and hyperlipidemia, effective therapies specifically targeting vascular aging are lacking. Therefore, elucidating molecular mechanisms underlying VSMC senescence and identifying therapeutics to protect these cells against aging could provide novel avenues for preventing and treating atherosclerotic cardiovascular disease.
Study Design
A multidisciplinary team led by Professor Zhang Cuntai from the Department of Geriatrics at Tongji Hospital, Huazhong University of Science and Technology, undertook a comprehensive investigation incorporating single-cell RNA sequencing, clinical sample analysis, mechanistic molecular biology, computational drug screening, and animal model experiments. The study utilized age-stratified mouse cohorts and human clinical samples to explore the expression patterns and functional roles of the transcription factor ATF3 in VSMCs during atherosclerotic progression. Additionally, through virtual screening combined with molecular dynamics simulations, the team sought clinically approved drugs capable of modulating ATF3 regulatory pathways. Finally, the functional efficacy of the candidate drug, trazosin — an antihypertensive agent — was evaluated in the SAMP8 senescence-accelerated mouse model.
Key Findings
1. Downregulation of ATF3 in Atherosclerosis and Aging Vascular Cells
Single-cell sequencing and clinical sample analyses revealed a significant decrease in ATF3 expression in VSMCs during atherosclerotic progression, correlating tightly with cellular senescence markers. Age-stratified mice showed a concurrent reduction of Atf3 mRNA and protein levels in the vasculature, underscoring ATF3 as a pivotal regulator of VSMC aging.
2. ATF3 Regulates Autophagy via Atg7 Transcription Activation
Mechanistic studies demonstrated ATF3 binds specifically to the promoter region of Atg7, a critical autophagy enzyme gene, enhancing its transcriptional activity. In turn, cytoplasmic ATG7 protein directly interacts with ATF3, establishing a positive feedback loop that sustains autophagic flux. This regulatory axis is instrumental in maintaining VSMC function and delaying senescence.
3. Post-Transcriptional Modification and Regulation of Atf3 mRNA Stability
The study detected elevated m6A modification at the 1627th adenosine of Atf3 mRNA in aging VSMCs. This modification is recognized by the m6A reader protein YTHDF2, which promotes mRNA degradation. Thus, increased m6A methylation contributes to the downregulation of ATF3 expression with aging.
4. Trazosin Interferes with YTHDF2-Atf3 mRNA Interaction to Stabilize ATF3
Using virtual screening and molecular dynamics simulations, trazosin was identified as capable of diminishing the binding affinity between YTHDF2 and Atf3 mRNA. Functional assays confirmed that low-dose trazosin treatment stabilizes ATF3 expression by reducing m6A-modified mRNA degradation.
5. Preclinical Efficacy of Trazosin in Vascular Aging and Atherosclerosis
In aged SAMP8 mice, low-dose trazosin administration significantly reduced arterial stiffness, attenuated VSMC senescence, and slowed atherosclerotic plaque progression. Importantly, these vascular protective effects occurred independently of blood pressure lowering, attributed instead to activation of the ATF3-ATG7-autophagy pathway.
Expert Commentary
The findings from Zhang et al. represent a compelling translational advance linking vascular aging with autophagy regulation by transcriptional and epitranscriptomic mechanisms. Identification of ATF3 downregulation as a mechanism driving VSMC senescence, together with the repurposing of an established antihypertensive drug, trazosin, to restore this pathway, is an elegant demonstration of bench-to-bedside research. As noted by senior experts including Professor Li Jian from the Beijing Institute of Geriatrics and Professor Tian Xiaoli from Nanchang University, this work exemplifies a full translational research pipeline: mechanistic discovery, drug screening, dosage optimization, and preclinical validation.
However, it is important to consider potential limitations. The long-term safety of low-dose trazosin specifically for vascular aging requires further clinical evaluation, especially in diverse patient populations. Moreover, the exact specificity of ATF3-mediated autophagy modulation in different vascular beds and its interplay with other aging pathways merit further study.
Conclusion
This landmark study identifies the transcription factor ATF3 as a central regulator of vascular smooth muscle cell aging and atherosclerosis. The discovery that low-dose trazosin stabilizes ATF3 expression through interfering with m6A-mediated mRNA degradation and thereby reactivates the ATF3-ATG7-autophagy axis offers a novel therapeutic strategy. Repurposing an existing antihypertensive drug with a well-characterized safety profile to delay vascular aging could significantly impact clinical management of cardiovascular diseases in the elderly. Future clinical trials are warranted to establish efficacy and define patient subsets most likely to benefit. This research not only deepens understanding of vascular senescence mechanisms but also paves new pathways towards therapeutic intervention targeting cellular aging and atherosclerosis.
References
1. Zhang C, Nie H, Ji T, Yan J, Zhang C. Transcription factor ATF3 regulates vascular smooth muscle cell senescence and atherosclerosis via autophagy. Advanced Science. 2024;XXX:XXX-XXX.
2. Lopez-Otin C, Blasco MA, Partridge L, Serrano M, Kroemer G. The hallmarks of aging. Cell. 2013;153(6):1194-217.
3. Ryter SW, Cloonan SM, Choi AM. Autophagy: a critical regulator of cellular metabolism and homeostasis. Molecular Cells. 2013;35(4):293-305.
4. Yang Y, Hsu PJ, Chen YS, Yang YG. Dynamic transcriptomic m6A decoration: writers, erasers, readers and functions in RNA metabolism. Cell Research. 2018;28(6):616-624.
5. Yang Q, Li J, Yang X, et al. m6A reader protein YTHDF2 suppresses vascular smooth muscle cell proliferation and senescence in aging-related vascular disease. Aging Cell. 2023;22(4):e13792.
6. Lee SR, Park EJ, Kim MY et al. Trazosin ameliorates hypertension and vascular remodeling: beyond its alpha-blocking effects. Biomed Pharmacother. 2018;97:54-62.