Adenosine monophosphate-activated protein kinase-α2 deficiency promotes vascular smooth muscle cell migration via S-Phase kinase-associated protein 2 upregulation and E-cadherin downregulation

Abstract

OBJECTIVE - : 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 roles of AMPK in VSMC migration and its underlying molecular mechanisms remain elusive. APPROACH AND RESULTS - : VSMC migration and the neointima formation were studied in cultured mouse VSMCs or in carotid artery ligation of wild-type C57BL/6J mice, AMPKα2, AMPKα1 homozygous-deficient (AMPKα2, AMPKα1) mice. Deletion of AMPKα2, but not AMPKα1, led to increased phosphorylation of both IkB kinase α and its downstream target nuclear factor kB2/p100 at serine 866/870. Consequently, phosphor-p100 at S866/870 bound with E3 ubiquitin ligase β-transducin repeat-containing protein resulting in the proteolytic processing of the p100 precursor and nuclear factor kB2/p52 induction. Interestingly, acetylation of histone H3 at lysine 56 mediated by histone deacetylase-3 reduction was enhanced significantly in AMPKα2 VSMCs compared with wild-type or AMPKα1 VSMCs. Moreover, the augmented association of p52/acetylation of histone H3 at lysine 56 with the promoter of ubiquitin E3 ligase, S-phase kinase-associated protein 2, was shown in AMPKα2 VSMCs by chromatin immunoprecipitation assay. Furthermore, AMPKα2 deletion caused S-phase kinase-associated protein 2-mediated E-cadherin downregulation. S-Phase kinase-associated protein 2 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. CONCLUSIONS - : We conclude that deletion of AMPKα2 causes aberrant VSMC migration with accelerated neointima formation in vivo. © 2013 American Heart Association, Inc.