Diabetes adversely affects macrophages during atherosclerotic plaque regression in mice.
Diabetes adversely affects macrophages during atherosclerotic plaque regression in mice.
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作者：
Parathath S;Grauer L;Huang LS;Sanson M;Distel E;Goldberg IJ;Fisher EA
糖尿病患者心血管风险增加。这些患者的动脉粥样硬化通常与斑块巨噬细胞增加和血脂异常有关。我们假设糖尿病动脉粥样硬化涉及削弱脂质减少对斑块巨噬细胞的有利作用的过程。 Reversa 小鼠是 LDL 受体缺陷的小鼠，会发生动脉粥样硬化。在有条件敲除编码微粒体甘油三酯转移蛋白的基因后，他们升高的血浆低密度脂蛋白水平得到降低。我们检查了对照小鼠和链脲佐菌素诱导的糖尿病 Reversa 小鼠在 LDL 降低后动脉粥样硬化斑块的形态和分子变化。骨髓来源的巨噬细胞也被用来研究高血糖介导的变化。 Reversa 小鼠接受西方饮食喂养 16 周，以形成斑块（基线）。脂质正常化四周后，与基线小鼠相比，对照（非糖尿病）小鼠的血浆胆固醇（-77%）、斑块胆固醇（-53%）和巨噬细胞标记物 CD68+ 阳性的斑块细胞（-73%）降低，但斑块胶原蛋白增加（+116%）。糖尿病小鼠的血浆胆固醇也同样降低，但胶原蛋白含量与基线相比仅增加了 34%；与对照小鼠相比，斑块胆固醇 (-30%) 和 CD68+ 细胞 (-41%) 的减少幅度较小。糖尿病（与对照）斑块 CD68+ 细胞还表现出更多的氧化应激和炎症基因表达，以及更少的抗炎 M2 巨噬细胞状态极化。许多体内研究结果都可以通过小鼠骨髓来源的巨噬细胞的高血糖得到重现。糖尿病阻碍了动脉粥样硬化小鼠的斑块消退（基于 CD68+ 斑块含量），并且在升高的血浆 LDL 降低后，斑块巨噬细胞特征发生了有利的变化。
Patients with diabetes have increased cardiovascular risk. Atherosclerosis in these patients is often associated with increased plaque macrophages and dyslipidemia. We hypothesized that diabetic atherosclerosis involves processes that impair favorable effects of lipid reduction on plaque macrophages. Reversa mice are LDL receptor–deficient mice that develop atherosclerosis. Their elevated plasma LDL levels are lowered after conditional knockout of the gene encoding microsomal triglyceride transfer protein. We examined the morphologic and molecular changes in atherosclerotic plaques in control and streptozotocin-induced diabetic Reversa mice after LDL lowering. Bone marrow–derived macrophages were also used to study changes mediated by hyperglycemia. Reversa mice were fed a western diet for 16 weeks to develop plaques (baseline). Four weeks after lipid normalization, control (nondiabetic) mice had reduced plasma cholesterol (−77%), plaque cholesterol (−53%), and plaque cells positive for macrophage marker CD68+ (−73%), but increased plaque collagen (+116%) compared with baseline mice. Diabetic mice had similarly reduced plasma cholesterol, but collagen content increased by only 34% compared with baseline; compared with control mice, there were lower reductions in plaque cholesterol (−30%) and CD68+ cells (−41%). Diabetic (vs. control) plaque CD68+ cells also exhibited more oxidant stress and inflammatory gene expression and less polarization toward the anti-inflammatory M2 macrophage state. Many of the findings in vivo were recapitulated by hyperglycemia in mouse bone marrow–derived macrophages. Diabetes hindered plaque regression in atherosclerotic mice (based on CD68+ plaque content) and favorable changes in plaque macrophage characteristics after the reduction of elevated plasma LDL.