科研之友
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摘要
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, AMPK2, AMPK1 homozygous-deficient (AMPK2(-/-), AMPK1(-/-)) mice. Deletion of AMPK2, but not AMPK1, led to increased phosphorylation of both IkB kinase and its downstream target nuclear factor kB2/p100 at serine 866/870. Consequently, phosphor-p100 at S866/870 bound with E3 ubiquitin ligase -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 AMPK2(-/-) VSMCs compared with wild-type or AMPK1(-/-) 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 AMPK2(-/-) VSMCs by chromatin immunoprecipitation assay. Furthermore, AMPK2 deletion caused S-phase kinase-associated protein 2-mediated E-cadherin downregulation. S-Phase kinase-associated protein 2 siRNA abolished the increased migration of AMPK2(-/-) VSMCs via E-cadherin upregulation. Finally, neointima formation after ligation of carotid artery was increased in AMPK2(-/-), but not AMPK1(-/-), mice. Conclusions We conclude that deletion of AMPK2 causes aberrant VSMC migration with accelerated neointima formation in vivo.
