Abstract 10710: Role of Endothelial AMPK in Endothelium-derived Hyperpolarizing Factor-Mediated Relaxations of Resistance Arteries in Mice
Background: We have recently demonstrated that endothelium-derived hyperpolarizing factor (EDHF) plays an important role in metabolic and microvascular endothelial functions in mice (Circ Res, 2012). Recently, the role of adenosine monophosphate-activated protein kinase (AMPK) has attracted much attention as an important regulator of metabolic functions. In this study, we thus aimed to examine the role of endothelial AMPK in EDHF-mediated relaxations in resistance arteries in mice.
Methods and Results: We newly developed mice lacking either endothelial α1 catalytic subunit alone (eAMPKα1-/-α2+/+) or both α1/α2 catalytic subunits of endothelial AMPK (eAMPKα1-/-α2-/-). Body weight and mean blood pressure were comparable between the eAMPKα1-/-α2-/- and eAMPKα1-/-α2+/+ mice and their littermates (26.8±1.7 vs. 29.6±1.4 g; 32.8±1.1 vs. 30.4±2.0 g and 91.8±6.5 vs. 101.1±8.3 mmHg; 89.8±7.7 vs. 95.3±6.6 mmHg, respectively). We used small mesenteric arteries isolated from those mice and each control littermate mice for organ chamber experiments (n=6 each). In intact mesenteric arteries with the endothelium from the control mice, acetylcholine (ACh) caused dose-dependent relaxations, which were resistant to indomethacin (10 μ M, an inhibitor of cyclooxygenase) and Nω-nitro-L-arginine (L-NNA, 100 μ M, an inhibitor of nitric oxide synthesis), but were abolished by the treatment with charybdotoxin (100 nM, an inhibitor of large conductance KCa channels) and apamin (1 μ M, an inhibitor of small conductance KCa channels), indicating the major role of EDHF. In contrast, endothelium-dependent relaxations to ACh were significantly impaired in both eAMPKα1-/-α2-/- and eAMPKα1-/-α2+/+ mice to the same extent and the remaining relaxations were inhibited by L-NNA and indomethacin, indicating the compensatory roles of prostacyclin and NO. In contrast, endothelium-independent relaxations to sodium nitroprusside were comparable among all the groups.
Conclusions: These results indicate that endothelial AMPK, especially α1 subunit of the enzyme, substantially mediates EDHF responses in mouse mesenteric arteries, suggesting the novel mechanism of endothelial AMPK-mediated metabolic control through EDHF responses.
- © 2012 by American Heart Association, Inc.