The potential of targeting adenosine 5'-monophosphate-activated protein kinase to treat peripheral artery disease: Evidence from preclinical mouse models.

BACKGROUND: Peripheral artery disease (PAD) affects over 200 million people worldwide, causing claudication, reduced mobility and quality of life, and increased adverse events risk. Currently, cilostazol is the only established medication for PAD symptoms. The adenosine 5'-monophosphate-activated protein kinase (AMPK) pathway is critical in energy production, particularly in high-turnover myeloid cells required for the compensatory revascularization response to limb ischemia. It also supports striated muscle repair needed to treat PAD-related ischemic myopathy. METHODS: A Systematic review and meta-analysis evaluated effects of AMPK activation or inhibition on limb perfusion following hind limb ischemia (HLI) in mouse models. The primary outcome was hind limb perfusion, and secondary outcomes included walking distance, limb loss, capillary density and phosphorylated endothelial nitric oxide synthase (p-eNOS). Twenty-five articles (401 experiment, 403 control mice) were included. Meta-analysis results were reported as standardized mean difference (SMD) or odds ratio (OR) and 95% confidence intervals (CI). Risk of bias was assessed using a tool incorporating Cochrane, ARRIVE and prior systematic review methods. RESULTS: AMPK activation improved hind limb perfusion (SMD 1.16, 95% CI: 0.87; 1.46, p < 0.001), reduced limb loss (OR 0.30, 95% CI: 0.12; 0.76, p = 0.011), increased capillary density and p-eNOS. Conversely, AMPK inhibition reduced hind limb perfusion (SMD -1.50, 95% CI: -2.00; -1.00, p < 0.001), decreased capillary density and p-eNOS. Low-to-moderate risk of bias. CONCLUSION: In mouse models of HLI, AMPK activation improved perfusion, reduced limb loss, and increased capillary density and p-eNOS, whereas inhibition had opposing effects. These findings support AMPK as a therapeutic target for PAD.