Abstract 13107: AMPKα2 Deletion Upregulates Skp2 via NF[[Unsupported Character - к]]B Activation
Proliferation and migration of vascular smooth muscle cells (VSMCs) is a critical event in the development and progression of several vasculopathies. Adenosine monophosphate-activated protein kinase (AMPK) is an energy sensor that has been shown to play a vital role in the cell proliferation. However, the role of AMPK in vascular remodeling and its underlying mechanisms are not fully known. We cultured mouse VSMCs isolated from wild-type (WT, C57BL/6J), and general either AMPKα2 or AMPKα1 homozygous deficient (AMPKα2−/−, AMPKα1−/−) mice, and conducted left carotid wire injury in mice with three different genotype. AMPKα2, not AMPKα1 deletion led to IκBα protein reduction, elevated NFκB p52 nuclear localization and DNA binding activity in mouse VSMCs. Furthermore, the mRNA and protein levels of ubiquitin E3 ligase SCFSkp2 were significantly increased in AMPKα2−/− VSMCs compared with either WT or AMPKα1−/− VSMCs. Interestingly, both p52 siRNA and NFκB inhibitor blocked SCFSkp2 induction in AMPKα2−/− VSMCs. In addition, Skp2 siRNA abolished the elevated VSMCs proliferation and migration in AMPKα2−/− VSMCs. Finally, both nuclear p52 and Skp2 staining were significantly enhanced in wire-injured carotid artery of AMPKα2−/− mice, which is associated with the more severe neointima formation in AMPKα2−/− mice after wire injury. These findings indicate that deletion of AMPKα2 rather than AMPKα1, mediates VSMCs proliferation, migration, and the resultant neointimal hyperplasia after vascular injury and this likely occurs via NFκB2/SCFSkp2. Our data suggest that AMPKα inactivation or deletion may account for VSMCs proliferation and migration, and consequently restenosis following vascular injury. Therefore, AMPK is likely to be a potential therapeutic target to inhibit the vascular remodeling that causes restenosis.
- © 2011 by American Heart Association, Inc.