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 300 million people worldwide, causing pain, reduced mobility and impaired quality of life, and increased risk of adverse events. Currently, cilostazol is the only established medication for PAD-related leg pain. The adenosine 5'-monophosphate-activated protein kinase (AMPK) pathway is critical in energy production, particularly in myeloid and muscle cells required for the compensatory response to limb ischemia. METHODS: A Systematic review and meta-analysis evaluating the effects of AMPK activation and inhibition on limb perfusion following hind limb ischemia (HLI) in mouse models was performed. The primary outcome was hind limb perfusion, and the secondary outcomes included walking distance, limb loss, capillary density and phosphorylated endothelial nitric oxide synthase (p-eNOS) levels. 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), and increased capillary density and p-eNOS levels. Conversely, AMPK inhibition reduced hind limb perfusion (SMD -1.50, 95% CI -2.00; -1.00, p < 0.001), and decreased capillary density and p-eNOS levels. The articles were found to have a low-to-moderate risk of bias. CONCLUSION: In mouse models of HLI, AMPK activation improved limb perfusion, reduced limb loss, and increased capillary density and p-eNOS levels, whereas inhibition had opposing effects. These findings support AMPK as a therapeutic target for limb ischemia.