AMPK-mediated prevention of vascular dysfunction with metformin: Experimental and population-based evidence

BACKGROUND AND PURPOSE: Metformin is increasingly recognised for its vasculoprotective effects, primarily through activation of AMP-activated protein kinase (AMPK). We combined population-based genetic epidemiology, with an ex vivo vascular model, to investigate the beneficial vascular effects of AMPK activation by metformin.

EXPERIMENTAL APPROACH: We used genetically proxied AMPK activation (GP-AMPK), based on 20 genome-wide significant single-nucleotide polymorphisms (SNPs), to assess associations with pulse wave velocity (PWV) and carotid intima-media thickness (cIMT). A two-sample Mendelian randomisation (MR) was performed to test the effect of GP-AMPK on a panel of inflammatory markers. We also developed a porcine coronary artery model of endothelial dysfunction to test the restorative effects of metformin on vascular function and related molecular signalling pathways.

KEY RESULTS: Higher GP-AMPK activation was associated with lower PWV, but not cIMT, in our epidemiological analysis (mean age 64.3 years, 43.8% female). Ex vivo, metformin restored endothelial relaxation in Angiotensin (Ang) II-treated vessels via endothelium-dependent hyperpolarisation (EDH) mechanisms, an effect abolished by AMPK inhibition. Western blotting confirmed the activation of AMPK (alpha 1 subunit) with metformin treatment. Inhibitor studies demonstrated a shift from NO-mediated to EDH-mediated relaxation with metformin. Molecular analyses showed reduced Ang II-induced expression of matrix remodelling (MMP1, MMP2) and senescence (P21) markers, as well as suppression of pro-inflammatory cytokines (Il-1β, Il-6, TNF-α), consistent with MR results.

CONCLUSION AND IMPLICATIONS: Metformin restored endothelial function and reduced vascular stiffness through an AMPK-EDH axis, highlighting a novel, potential therapeutic mechanism for early vascular dysfunction independent of glycaemic effects.