The dysregulation of myeloid-derived cell metabolism can drive atherosclerosis. AMP-activated protein kinase (AMPK) controls various aspects of macrophage dynamics and lipid homeostasis, which are important during atherogenesis. Using LysM-Cre to drive the deletion of both the α1 and α2 catalytic subunits (MacKO), we aimed to clarify the role of myeloid-specific AMPK signaling in male and female mice made acutely atherosclerotic by injection of adeno-associated virus vector encoding a gain-of-function mutant PCSK9 (PCSK9-AAV) and Western diet-feeding. After 6 weeks of Western diet feeding, mice received a daily injection of either the AMPK activator A-769662 or a vehicle control for an additional 6 weeks. Following this (12 weeks total), we assessed myeloid cell populations and differences between genotype or sex were not observed. Similarly, aortic sinus plaque size, lipid staining and necrotic area did not differ in male and female MacKO mice compared to their littermate floxed controls. Moreover, therapeutic intervention with A-769662 showed no treatment effect. There were also no observable differences in the amount of circulating total cholesterol or triglyceride, and only minor differences in the levels of inflammatory cytokines between groups. Finally, CD68+ area and markers of autophagy showed no effect of either lacking AMPK signaling or AMPK activation. Our data suggest that while defined roles for each catalytic AMPK subunit have been identified, global deletion of myeloid AMPK signaling does not significantly impact atherosclerosis. Additionally, these findings suggest that intervention with the first-generation AMPK activator A-769662 is not able to stem the progression of atherosclerosis.

中文翻译：

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骨髓缺失和 AMPK 的治疗激活不会改变雄性或雌性小鼠的动脉粥样硬化。


骨髓源性细胞代谢失调可导致动脉粥样硬化。 AMP 激活蛋白激酶 (AMPK) 控制巨噬细胞动力学和脂质稳态的各个方面，这在动脉粥样硬化形成过程中非常重要。使用 LysM-Cre 驱动 α1 和 α2 催化亚基 (MacKO) 的删除，我们旨在阐明骨髓特异性 AMPK 信号在通过注射编码 a 的腺相关病毒载体而导致急性动脉粥样硬化的雄性和雌性小鼠中的作用。功能获得突变体 PCSK9 (PCSK9-AAV) 和西方饮食喂养。经过 6 周的西方饮食喂养后，小鼠在接下来的 6 周内每天注射 AMPK 激活剂 A-769662 或载体对照。此后（总共 12 周），我们评估了骨髓细胞群，没有观察到基因型或性别之间的差异。同样，与同窝的 floxed 对照组相比，雄性和雌性 MacKO 小鼠的主动脉窦斑块大小、脂质染色和坏死面积没有差异。此外，A-769662 的治疗干预未显示治疗效果。各组之间循环总胆固醇或甘油三酯的量也没有明显差异，炎症细胞因子水平也只有微小差异。最后，CD68+ 区域和自噬标记物显示缺乏 AMPK 信号传导或 AMPK 激活没有影响。我们的数据表明，虽然已经确定了每个催化 AMPK 亚基的明确作用，但骨髓 AMPK 信号传导的整体删除并不会显着影响动脉粥样硬化。此外，这些研究结果表明，第一代 AMPK 激活剂 A-769662 的干预无法阻止动脉粥样硬化的进展。