Abstract 273: Glycogen Depletion During Hypoxia Results in Enhanced AMPK Phosphorylation and Diminished Smooth Muscle Contractility in Human Saphenous Vein

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Objectives: Hypoxia promotes vasodilation of coronary arteries as a protective response to improve blood flow to the myocardium. Although diminished formation of ATP and enhanced phosphorylation/activation of AMP-activated protein kinase (AMPK) in vascular smooth muscle are known to mediate hypoxia-induced vasorelaxation, the contribution of glycogen toward AMPK phosphorylation and contractility remains unclear.

Methods: Using surgically-removed endothelium-denuded human saphenous vein segments ex vivo, the present study has examined serotonin (5-HT)-induced smooth muscle contractility by isometric tension measurements and AMPK phosphorylation by immunoblot analysis under normoxic (95% O2/5% CO2) and hypoxic conditions (95% N2/5% CO2, 30 min).

Results: Under normoxic glycogen-enriched conditions, the maximal contractile response (Emax) and sensitivity (pEC50) to 5-HT-induced contractility were 145 ± 3% and 6.7 ± 0.2, respectively (n = 4). Induction of hypoxia diminished the glycogen content by ~95% (3.7 ± 1 under hypoxia versus 73.6 ± 5 μg/mg protein under normoxia; n = 2). Importantly, glycogen depletion led to diminution in 5-HT-induced maximal contractility to 37 ± 11% with an accompanying exaggerated increase in AMPK phosphorylation, compared with normoxic conditions (n = 4). Inclusion of exogenous D-glucose (5.5 mM) prevented the exaggerated increase in AMPK phosphorylation thereby restoring 5-HT-induced maximal contractility to 125 ± 6% (n = 4). Parallel studies that included either L-glucose or 2-deoxy-D-glucose (non-metabolizable forms of glucose) did not show any changes in contractility or AMPK phosphorylation.

Conclusion: The present findings suggest that depletion of smooth muscle glycogen during hypoxia may limit the availability of intracellular glucose in vein grafts, thereby enhancing AMPK phosphorylation to promote vasorelaxation.

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