Metformin Stabilizes the Abdominal Aorta in Aneurysm by Restoring VSMC Mitochondrial Homeostasis via the AMPK–SIRT1–PGC-1α Axis
Abstract
BACKGROUND: Abdominal aortic aneurysm (AAA) is a life-threatening condition with >80% mortality upon rupture and no effective pharmacotherapy available. Despite epidemiological evidence linking metformin use to reduced AAA progression, its mechanism remains elusive. Notably, peroxisome proliferator-activated receptor γ coactivator 1α (PGC-1α, encoded by Ppargc1a ) is downregulated in human AAA, yet its functional role in metformin’s protection is unknown.
METHODS: We employed porcine pancreatic elastase (PPE)-induced murine AAA, VSMC-specific Ppargc1a knockout ( Ppargc1a VSMC-KO ), primary VSMC senescence models, and pharmacological inhibition (Compound C for AMPK; Ex-527 for SIRT1) to define the AMPK–SIRT1–PGC-1α axis.
RESULTS: Metformin significantly inhibited AAA expansion, suppressed VSMC senescence (p53/p21↓, SA-β-gal↓), and preserved contractile phenotype (SMTN↑, IL-6/TNF-α↓). Crucially, all benefits were abrogated in Ppargc1a VSMC-KO mice, which exhibited accelerated aneurysm growth, mitochondrial fragmentation, ATP depletion, and ROS accumulation. Mechanistically, metformin activated AMPK/SIRT1 to upregulate PGC-1α; AMPK or SIRT1 inhibition blocked this cascade and reversed protection.
CONCLUSION: Metformin restrains AAA by restoring VSMC mitochondrial homeostasis via the AMPK/SIRT1→PGC-1α axis, positioning PGC-1α as a non-redundant, cell-autonomous guardian against vascular degeneration. These findings provide a mechanistic foundation for repurposing metformin and…
How strong is the evidence?
Evidence Hub reads this as a preprint, done in animal, not in people. Its evidence level is 5 of 5 (Very low · case / narrative / animal / in vitro / in silico). Case reports, narrative reviews, and animal, cell or computer-model studies give the weakest evidence for human health.
Read the paper
Related studies
- Metformin as an adjuvant in breast cancer treatment
- Metformin Lysosomal Targeting: A Novel Aspect to Be Investigated for Metformin Repurposing in Neurodegenerative Diseases?
- Aberrant HSF1 signaling activation underlies metformin amelioration of myocardial infarction in mice
- Metformin induces ZFP36 by mTORC1 inhibition in cervical cancer-derived cell lines
- Protein Interaction Network for Identifying Vascular Response of Metformin (Oral Antidiabetic)
- Preventing Long COVID With Metformin
Go deeper in Evidence Hub
Evidence Hub adds a study data sheet (design, sample size, evidence level, key numbers), an AI summary and a chat grounded in the paper's text.