AMPK alpha 2 deletion exacerbates neointima formation by upregulating Skp2 in vascular smooth muscle cells
Rationale: Adenosine monophosphate-activated protein kinase (AMPK), a metabolic and redox sensor, is reported to suppress cell proliferation of nonmalignant and tumor cells. Whether AMPK alpha alters vascular neointima formation induced by vascular injury is unknown.
Objective: The aim of this study was to determine the roles of AMPK alpha in the development of vascular neointima hyperplasia and to elucidate the underlying mechanisms.
Methods and Results: Vascular smooth muscle cell (VSMC) proliferation and neointimal hyperplasia were evaluated in cultured VSMCs and wire-injured mouse carotid arteries from wild-type (WT, C57BL/ 6J), AMPK alpha 2(-/-), and AMPK alpha 1(-/-) mice. Mouse VSMCs derived from aortas of AMPK alpha 2(-/-) mice exhibited increased proliferation compared with either WT or AMPK alpha 1(-/-) VSMCs. Further, deletion of AMPK alpha 2 but not AMPK alpha 1 reduced the level of p27Kip1, a cyclin-dependent kinase inhibitor, and increased the level of S-phase kinase-associated protein 2 (Skp2), a known E3 ubiquitin ligase for p27Kip1, through activation of p52 nuclear factor kappa B (NF-kappa B)-2. Moreover, either pharmacological (ie, through compound C) or genetical (ie, through AMPK alpha 2-specific siRNA) inhibition of AMPK decreased p27Kip1 levels but increased the abundance of Skp2 in human VSMCs. Furthermore, gene silencing of Skp2 reversed the levels of p27Kip1 and VSMCs proliferation. Finally, neointima formation after mechanical arterial injury was increased in AMPK alpha 2(-/-) but not AMPK alpha 1(-/-) mice.
Conclusions: These findings indicate that deletion of AMPK alpha 2 through p52-Skp2-mediated ubiquintination and degradation of p27Kip1 accentuates neointimal hyperplasia in response to wire injury. (Circ Res. 2011; 109: 1230-1239.)
Song, P., Wang, S., He, C., Wang, S., Liang, B., Viollet, B., & Zou, M-H. (2011). AMPK alpha 2 deletion exacerbates neointima formation by upregulating Skp2 in vascular smooth muscle cells. Circulation Research, 109(11), 1230-1239. DOI: 10.1161/CIRCRESAHA.111.250423