Enhanced Akt3 kinase activity reduces atherosclerosis in hyperlipidemic mice in a gender-dependent manner.
Enhanced Akt3 kinase activity reduces atherosclerosis in hyperlipidemic mice in a gender-dependent manner.
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DOI：
10.1016/j.jbc.2023.105425
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发表时间：
2023-12
影响因子：
4.8
通讯作者：
Podrez, Eugene A.
中科院分区：
文献类型：
--
作者：
Zhang, Lifang;Altemus, Jessica;Ding, Liang;Cherepanova, Olga;Byzova, Tatiana, V;Podrez, Eugene A.
Akt 3是丝氨酸/苏氨酸蛋白激酶B（AKT）家族的三个成员之一，其调节多种细胞过程。我们先前已经证明，小鼠中Akt 3的整体敲除以巨噬细胞依赖性方式促进动脉粥样硬化形成。Akt 3激酶活性增强是否影响动脉粥样硬化发生尚不清楚。在这项研究中，我们将易患动脉粥样硬化的ApoE−/−小鼠与具有增强的Akt 3激酶活性（Akt 3 nmf 350）的小鼠品系杂交，并评估动脉粥样硬化病变形成和巨噬细胞在动脉粥样硬化形成中的作用。在喂食西式饮食的Apoe-/-/Akt 3 nmf 350小鼠中观察到动脉粥样硬化病变面积和病变中巨噬细胞积聚显着减少。使用带有ApoE−/−/Akt 3 nmf 350骨髓或ApoE−/−骨髓细胞的嵌合ApoE−/−小鼠进行的实验表明，骨髓来源细胞中Akt 3活性的增强具有动脉粥样硬化保护作用。Akt 3 nmf 350的动脉粥样硬化保护作用在雄性小鼠中更明显。与此结果一致，雄性而非雌性ApoE−/−/Akt 3 nmf 350小鼠的巨噬细胞减少了促炎细胞因子IL-6、MCP 1、TNF-α和MIP-1α的释放。与ApoE−/−小鼠相比，ApoE−/−/Akt 3 nmf 350雄性小鼠动脉粥样硬化病变中的IL-6和TNF-α水平也降低。来自雄性ApoE−/−/Akt 3 nmf 350小鼠的巨噬细胞在体外和体内对细胞凋亡的抵抗力也更强，并且在体外倾向于具有更明显的M2极化。这些发现表明，巨噬细胞中Akt 3激酶活性的增强以性别依赖的方式保护高脂血症小鼠免于动脉粥样硬化。
Akt3 is one of the three members of the serine/threonine protein kinase B (AKT) family, which regulates multiple cellular processes. We have previously demonstrated that global knockout of Akt3 in mice promotes atherogenesis in a macrophage-dependent manner. Whether enhanced Akt3 kinase activity affects atherogenesis is not known. In this study, we crossed atherosclerosis-prone ApoE−/− mice with a mouse strain that has enhanced Akt3 kinase activity (Akt3nmf350) and assessed atherosclerotic lesion formation and the role of macrophages in atherogenesis. Significant reduction in atherosclerotic lesion area and macrophage accumulation in lesions were observed in ApoE−/−/Akt3nmf350 mice fed a Western-type diet. Experiments using chimeric ApoE−/− mice with either ApoE−/−/Akt3nmf350 bone marrow or ApoE−/− bone marrow cells showed that enhanced Akt3 activity specifically in bone marrow-derived cells is atheroprotective. The atheroprotective effect of Akt3nmf350 was more pronounced in male mice. In line with this result, the release of the pro-inflammatory cytokines IL-6, MCP1, TNF-α, and MIP-1α was reduced by macrophages from male but not female ApoE−/−/Akt3nmf350 mice. Levels of IL-6 and TNF-α were also reduced in atherosclerotic lesions of ApoE−/−/Akt3nmf350 male mice compared to ApoE−/− mice. Macrophages from male ApoE−/−/Akt3nmf350 mice were also more resistant to apoptosis in vitro and in vivo and tended to have more pronounced M2 polarization in vitro. These findings demonstrated that enhanced Akt3 kinase activity in macrophages protects mice from atherosclerosis in hyperlipidemic mice in a gender-dependent manner.
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