AMPKα2 deletion exacerbates neointima formation by upregulating Skp2 in vascular smooth muscle cells.
AMPKα2 deletion exacerbates neointima formation by upregulating Skp2 in vascular smooth muscle cells.
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DOI：
10.1161/circresaha.111.250423
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发表时间：
2011-11-11
影响因子：
20.1
通讯作者：
Zou MH
中科院分区：
文献类型：
--
作者：
Song P;Wang S;He C;Wang S;Liang B;Viollet B;Zou MH
腺苷一磷酸活化蛋白激酶（AMPK）是一种代谢和氧化还原传感器，据报道可抑制非恶性肿瘤和肿瘤细胞的细胞增殖。AMPKα是否改变血管损伤诱导的血管新生内膜形成尚不清楚。本研究旨在探讨AMPKα在血管新生内膜增生中的作用及其机制。在野生型（WT，C57 BL/6 J）、AMPKα2−/−和AMPKα1−/− VSMC的培养VSMC和钢丝损伤小鼠颈动脉中评价了VSMC增殖和新生内膜增生。与WT或AMPKα1−/− VSMCs相比，AMPKα2−/−小鼠血管平滑肌细胞的增殖增加。此外，AMPKα2（而非AMPKα1）的缺失通过激活p52核因子κ B（NF-κB）-2，降低了p27 Kip 1（一种环蛋白依赖性激酶抑制剂）的水平，并增加了S期激酶相关蛋白2（Skp 2）（一种已知的p27 Kip 1的E3泛素连接酶）的水平。此外，无论是药理学的（即，通过化合物C）或遗传（即，通过AMPKα2特异性siRNA）抑制AMPK降低人VSMCs中p27 Kip 1水平，但增加Skp 2丰度。此外，Skp 2基因沉默逆转了p27 Kip 1和VSMCs增殖的水平。最后，AMPKα2−/−小鼠机械性动脉损伤后新生内膜形成增加，但AMPKα1−/−小鼠没有。这些结果表明，通过p52-Skp 2介导的泛素化和p27 Kip 1降解导致AMPKα2缺失，加重了对导丝损伤的新生内膜增生。
Adenosine monophosphate-activated protein kinase (AMPK), a metabolic and redox sensor, is reported to suppress cell proliferation of non-malignant and tumor cells. Whether AMPKα alters vascular neointima formation induced by vascular injury is unknown. The aim of this study was to determine the roles of AMPKα in the development of vascular neointima hyperplasia and to elucidate the underlying mechanisms. Vascular smooth muscle cells (VSMCs) proliferation and neointimal hyperplasia were evaluated in cultured VSMCs and wire-injured mouse carotid arteries from wild-type (WT, C57BL/6J), AMPKα2−/−, and AMPKα1−/− VSMCs. Mouse VSMCs derived from aortas of AMPKα2−/− mice exhibited increased proliferation compared to either WT or AMPKα1−/− VSMCs. Further, deletion of AMPKα2, but not AMPKα1, reduced the level of p27Kip1, acyclin-dependent kinase inhibitor, and increased the level of S-phase kinase-associated protein 2 (Skp2), a known E3 ubiquitin ligase for p27Kip1, via activation of p52 nuclear factor kappa B (NF-κB)-2. Moreover, either pharmacological (i.e., via compound C) or genetical (i.e., via AMPKα2-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 AMPKα2−/−, but not AMPKα1−/−, mice. These findings indicate that deletion of AMPKα2 via p52-Skp2-mediated ubiquintination and degradation of p27Kip1 accentuates neointimal hyperplasia in response to wire injury.