Ablation of Adenosine Monophosphate-Activated Protein Kinase α1 in Vascular Smooth Muscle Cells Promotes Diet-Induced Atherosclerotic Calcification In Vivo

安普克 血管平滑肌 内科学 内分泌学 AMP活化蛋白激酶 蛋白激酶A 化学 载脂蛋白E 运行x2 相扑蛋白 细胞生物学 磷酸化 生物 医学 泛素 生物化学 转录因子 基因 疾病 平滑肌
作者
Zhejun Cai,Ding Ye,Miao Zhang,Qiulun Lu,Shengnan Wu,Huaiping Zhu,Ping Song,Ming-Hui Zou
出处
期刊:Circulation Research [Ovid Technologies (Wolters Kluwer)]
卷期号:119 (3): 422-433 被引量:91
标识
DOI:10.1161/circresaha.116.308301
摘要

Atherosclerotic calcification is highly linked with plaque rapture. How calcification is regulated is poorly characterized.We sought to determine the contributions of AMP-activated protein kinase (AMPK) in atherosclerotic calcification.Aortic calcification was evaluated in aortic roots and brachiocephalic arteries of atherosclerotic prone ApoE(-/-) mice or in mice with dual deficiencies of ApoE and AMPKα isoforms in whole body (ApoE(-/-)/AMPKα1(-/-) and ApoE(-/-)/AMPKα2(-/-)) or vascular smooth muscle cell (VSMC)-specific or macrophage-specific knockout of AMPKα1 fed with Western diet for 24 weeks. Genetic deficiency of AMPKα1 but not of AMPKα2 promoted atherosclerotic calcification and the expression of Runx2 (Runt-related transcription factor). Conversely, chronic administration of metformin, which activated AMPK, markedly reduced atherosclerotic calcification and Runx2 expression in ApoE(-/-) mice but had less effects in ApoE(-/-)/AMPKα1(-/-) mice. Furthermore, VSMC-specific but not macrophage-specific ablation of AMPKα1 promoted aortic calcification in vivo. Ablation of AMPKα1 in VSMC prevented Runx2 from proteasome degradation in parallel with aberrant osteoblastic differentiation of VSMC, whereas AMPK activation promoted Runx2 post-translational modification by small ubiquitin-like modifier (SUMO, SUMOylation), which is associated with its instability. Mechanically, we found that AMPKα1 directly phosphorylated protein inhibitor of activated STAT-1 (PIAS1), the SUMO E3-ligase of Runx2, at serine 510, to promote its SUMO E3-ligase activity. Finally, mutation of protein inhibitor of activated STAT-1 at serine 510 suppressed metformin-induced Runx2 SUMOylation and subsequently prevented metformin's effect on reducing oxidized low-density lipoprotein-triggered Runx2 expression in VSMC.AMPKα1 phosphorylated protein inhibitor of activated STAT-1 to promote Runx2 SUMOylation and subsequently lead to its instability. AMPKα1 deficiency in VSMC increased Runx2 expression and promoted atherosclerotic calcification in vivo.
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