Abstract 9547: AMPKa2 Deletion Promotes Vascular Smooth Muscle Cell Migration via Skp2 Upregulation and E-cadherin Downregulation
The abnormal proliferation and migration of vascular smooth muscle cells (VSMCs) are critical events in the progression of several vasculopathologies. Adenosine monophosphate-activated protein kinase (AMPK) has been shown to play a pivotal role in cellular proliferation and migration. However, the exact role of AMPK in VSMCs migration and its underlying molecular mechanisms remain elusive. We cultured mouse VSMCs isolated from wild-type (WT) C57BL/6J mice and either AMPKα2 or AMPKα1 homozygous-deficient (AMPKα2-/-, AMPKα1-/-) mice to investigate the molecular mechanisms of VSMCs migration. Deletion of AMPKα2, but not AMPKα1, led to increased phosphorylation of IκB kinase α (IκKα) and its downstream target nuclear factor κB2 (NFκB2)/p100 at serine 866/870. This resulted in pp100-S866/870 association with E3 ubiquitin ligase β-transducin repeat-containing protein (β-TrCP), which contributed to NFκB2/p52 induction from the proteolytic processing of the p100 precursor. Interestingly, acetylation of histone H3 at lysine 56 (AcH3-K56) resulted in association with histone deacetylase 3 (HDAC3) which was significantly enhanced in AMPKα2-/- VSMCs compared with either WT or AMPKα1-/- VSMCs. Moreover, the augmented association of p52/AcH3-K56 with the promoter of ubiquitin E3 ligase S-phase kinase-associated protein 2 (Skp2) was shown in AMPKa2-/- VSMCs by ChIP assay. Furthermore, AMPKα2 deletion caused E-cadherin downregulation, which is mediated by Skp2 and the ubiquitin-proteasome system. Skp2 siRNA abolished the increased migration of AMPKα2-/- VSMCs via E-cadherin upregulation. Finally, neointima formation after ligation of carotid artery was increased in AMPKα2-/-, but not AMPKα1-/-, mice and was associated with increased AcH3-K56 as well as reduction of both HDAC3 and E-cadherin. This compelling evidence indicates that deletion of AMPKα2, rather than AMPKα1, mediates VSMCs migration and the resultant neointimal formation after vascular injury. These events appear to occur via the NFκB2/Skp2/E-cadherin pathway.
- © 2013 by American Heart Association, Inc.