Akt3 Deficiency in Macrophages Promotes Foam Cell Formation and Atherosclerosis in Mice

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• 作者：Liang Ding¹ ; Sudipta Biswas¹ ; Richard  ; E. Morton² ; Jonathan  ; D. Smith² ; Nissim Hay³ ; Tatiana V. Byzova¹ ; Maria Febbraio¹ ; Eugene  ; A. Podrez¹ ; ^{podreze@ccf.org}
• 刊名：Cell Metabolism
• 出版年：2012
• 期刊代码：46_15504131
• 类别：med
• 出版时间：6 June, 2012
• 卷：15
• 期：6
• 页码：861-872
• 文件大小：1673 K

摘要

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Summary

Akt, a serine-threonine protein kinase, exists as three聽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^{鈭?鈭?/sup> mice, we demonstrated a macrophage-dependent, atheroprotective role for Akt3. In聽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.}