Department of Molecular Cardiology, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195, USA.
Cell Metab. 2012 Jun 6;15(6):861-72. doi: 10.1016/j.cmet.2012.04.020. Epub 2012 May 24.
Akt, a serine-threonine protein kinase, exists as three isoforms. The Akt signaling pathway controls multiple cellular functions in the cardiovascular system, and the atheroprotective endothelial cell-dependent role of Akt1 has been recently demonstrated. The role of Akt3 isoform in cardiovascular pathophysiology is not known. We explored the role of Akt3 in atherosclerosis using mice with a genetic ablation of the Akt3 gene. Using hyperlipidemic ApoE(-/-) mice, we demonstrated a macrophage-dependent, atheroprotective role for Akt3. In vitro experiments demonstrated differential subcellular localization of Akt1 and Akt3 in macrophages and showed that Akt3 specifically inhibits macrophage cholesteryl ester accumulation and foam cell formation, a critical early event in atherogenesis. Mechanistically, Akt3 suppresses foam cell formation by reducing lipoprotein uptake and promoting ACAT-1 degradation via the ubiquitin-proteasome pathway. These studies demonstrate the nonredundant atheroprotective role for Akt3 exerted via the previously unknown link between the Akt signaling pathway and cholesterol metabolism.
Akt 是一种丝氨酸/苏氨酸蛋白激酶，存在三种同工型。Akt 信号通路控制心血管系统中的多种细胞功能，最近已经证实 Akt1 具有抗动脉粥样硬化的内皮细胞依赖性作用。Akt3 同工型在心血管病理生理学中的作用尚不清楚。我们使用 Akt3 基因敲除的小鼠来探索 Akt3 在动脉粥样硬化中的作用。利用高脂血症 ApoE(-/-) 小鼠，我们证明了 Akt3 具有巨噬细胞依赖性的抗动脉粥样硬化作用。体外实验表明 Akt1 和 Akt3 在巨噬细胞中的亚细胞定位存在差异，并表明 Akt3 特异性抑制巨噬细胞胆固醇酯的积累和泡沫细胞的形成，这是动脉粥样硬化形成的一个关键早期事件。从机制上讲，Akt3 通过减少脂蛋白摄取和通过泛素-蛋白酶体途径促进 ACAT-1 降解来抑制泡沫细胞的形成。这些研究表明，Akt3 通过 Akt 信号通路和胆固醇代谢之间的未知联系发挥非冗余的抗动脉粥样硬化作用。
