| First Author | Song P | Year | 2013 |
| Journal | Arterioscler Thromb Vasc Biol | Volume | 33 |
| Issue | 12 | Pages | 2800-9 |
| PubMed ID | 24115035 | Mgi Jnum | J:222210 |
| Mgi Id | MGI:5644127 | Doi | 10.1161/ATVBAHA.113.301869 |
| Citation | Song P, et al. (2013) Adenosine monophosphate-activated protein kinase-alpha2 deficiency promotes vascular smooth muscle cell migration via S-phase kinase-associated protein 2 upregulation and E-cadherin downregulation. Arterioscler Thromb Vasc Biol 33(12):2800-9 |
| abstractText | 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, AMPKalpha2, AMPKalpha1 homozygous-deficient (AMPKalpha2(-/-), AMPKalpha1(-/-)) mice. Deletion of AMPKalpha2, but not AMPKalpha1, led to increased phosphorylation of both Ismall ka, CyrillicB kinase alpha and its downstream target nuclear factor small ka, CyrillicB2/p100 at serine 866/870. Consequently, phosphor-p100 at S866/870 bound with E3 ubiquitin ligase beta-transducin repeat-containing protein resulting in the proteolytic processing of the p100 precursor and nuclear factor small ka, CyrillicB2/p52 induction. Interestingly, acetylation of histone H3 at lysine 56 mediated by histone deacetylase-3 reduction was enhanced significantly in AMPKalpha2(-/-) VSMCs compared with wild-type or AMPKalpha1(-/-) 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 AMPKalpha2(-/-) VSMCs by chromatin immunoprecipitation assay. Furthermore, AMPKalpha2 deletion caused S-phase kinase-associated protein 2-mediated E-cadherin downregulation. S-Phase kinase-associated protein 2 siRNA abolished the increased migration of AMPKalpha2(-/-) VSMCs via E-cadherin upregulation. Finally, neointima formation after ligation of carotid artery was increased in AMPKalpha2(-/-), but not AMPKalpha1(-/-), mice. CONCLUSIONS: We conclude that deletion of AMPKalpha2 causes aberrant VSMC migration with accelerated neointima formation in vivo. |
