Myeloid Deletion of α1AMPK Exacerbates Atherosclerosis in LDL Receptor Knockout (LDLRKO) Mice.
Myeloid Deletion of α1AMPK Exacerbates Atherosclerosis in LDL Receptor Knockout (LDLRKO) Mice.
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作者：
Cao Q;Cui X;Wu R;Zha L;Wang X;Parks JS;Yu L;Shi H;Xue B
巨噬细胞炎症标志着动脉粥样硬化形成的所有阶段，AMPK是巨噬细胞炎症的调节剂。因此，我们在LDL受体敲除（LDLRKO）的基础上产生了髓样α1AMPK敲除（MAKO）小鼠，以研究髓样α1AMPK缺失是否加重动脉粥样硬化。当喂食致动脉粥样硬化饮食时，与LDLRKO小鼠相比，MAKO/LDLRKO小鼠显示出加重的动脉粥样硬化。为了确定潜在的病理生理学途径，我们表征了MAKO/LDLRKO小鼠中的巨噬细胞炎症/趋化性和脂质/胆固醇代谢。α1AMPK髓样缺失增加巨噬细胞炎症基因表达，增强巨噬细胞迁移和粘附内皮细胞。值得注意的是，MAKO/LDLRKO小鼠还显示出较高的循环趋化活性Ly-6Chigh单核细胞组成，增强的动脉粥样硬化斑块趋化因子表达和单核细胞募集到斑块中，导致动脉粥样硬化斑块巨噬细胞含量增加和炎症。MAKO/LDLRKO小鼠还表现出更高的血浆LDL和VLDL胆固醇含量，增加的循环载脂蛋白B（apo B）水平和更高的肝脏apo B表达。结论巨噬细胞α1AMPK缺陷促进LDLRKO小鼠动脉粥样硬化的形成，并与巨噬细胞炎症和高胆固醇血症有关，巨噬细胞α1AMPK可能成为防治动脉粥样硬化的治疗靶点。
Macrophage inflammation marks all stages of atherogenesis, and AMPK is a regulator of macrophage inflammation. We therefore generated myeloid α1AMPK knockout (MAKO) mice on the LDL receptor knockout (LDLRKO) background to investigate whether myeloid deletion of α1AMPK exacerbates atherosclerosis. When fed an atherogenic diet, MAKO/LDLRKO mice displayed exacerbated atherosclerosis compared with LDLRKO mice. To determine the underlying pathophysiological pathways, we characterized macrophage inflammation/chemotaxis and lipid/cholesterol metabolism in MAKO/LDLRKO mice. Myeloid deletion of α1AMPK increased macrophage inflammatory gene expression and enhanced macrophage migration and adhesion to endothelial cells. Remarkably, MAKO/LDLRKO mice also displayed higher composition of circulating chemotaxically active Ly-6Chigh monocytes, enhanced atherosclerotic plaque chemokine expression, and monocyte recruitment into plaques, leading to increased atherosclerotic plaque macrophage content and inflammation. MAKO/LDLRKO mice also exhibited higher plasma LDL and VLDL cholesterol content, increased circulating apolipoprotein B (apoB) levels, and higher liver apoB expression. We conclude that macrophage α1AMPK deficiency promotes atherogenesis in LDLRKO mice and is associated with enhanced macrophage inflammation and hypercholesterolemia and that macrophage α1AMPK may serve as a therapeutic target for prevention and treatment of atherosclerosis.