Hyperglycemia Impairs Atherosclerosis Regression in Mice
Hyperglycemia Impairs Atherosclerosis Regression in Mice
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DOI：
10.1016/j.ajpath.2013.08.019
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发表时间：
2013-12-01
影响因子：
6
通讯作者：
Raffai, Robert L.
中科院分区：
文献类型：
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作者：
Gaudreault, Nathalie;Kumar, Nikit;Raffai, Robert L.
已知糖尿病患者更易患动脉粥样硬化及其相关的心血管并发症。然而，高血糖对动脉粥样硬化消退的影响仍不清楚。我们假设高血糖通过调节病变巨噬细胞的生物学功能来损害动脉粥样硬化的消退。HypoE（Apoe（h/h）Mx 1-Cre）小鼠表达低水平的载脂蛋白E（apoE），并在喂食高脂饮食时发生动脉粥样硬化。在这些小鼠中，通过改变饮食和恢复apoE表达诱导的血浆脂质降低，动脉粥样硬化消退。我们检查了退化病变的形态学特征，并评估了正常血糖和高血糖HypoE小鼠中用激光捕获显微切割分离的病变巨噬细胞的生物学功能。在高脂血症逆转后，链脲佐菌素治疗诱导的高脂血症损害了病变大小的缩小（36%对14%）和脂质损失（38%对26%）。然而，两组小鼠的病变巨噬细胞含量和重塑的减少是相似的。基因表达分析显示，高血糖通过调节动脉粥样硬化消退过程中损伤巨噬细胞中的ATP结合盒A1、ATP结合盒G1、清道夫受体B家族成员（CD 36）、清道夫受体B1和伤口愈合途径损害胆固醇转运。高脂血症损害动脉粥样硬化病变在血浆脂质降低时的脂质的尺寸减小和损失，而不显著影响血管壁的重塑。
Diabetic patients are known to be more susceptible to atherosclerosis and its associated cardiovascular complications. However, the effects of hyperglycemia on atherosclerosis regression remain unclear. We hypothesized that hyperglycemia impairs atherosclerosis regression by modulating the biological function of lesional macrophages. HypoE (Apoe(h/h)Mx1-Cre) mice express low levels of apolipoprotein E (apoE) and develop atherosclerosis when fed a high-fat diet. Atherosclerosis regression occurs in these mice upon plasma lipid lowering induced by a change in diet and the restoration of apoE expression. We examined the morphological characteristics of regressed lesions and assessed the biological function of lesional macrophages isolated with laser-capture microdissection in euglycemic and hyperglycemic HypoE mice. Hyperglycemia induced by streptozotocin treatment impaired lesion size reduction (36% versus 14%) and Lipid loss (38% versus 26%) after the reversal of hyperlipidemia. However, decreases in lesional macrophage content and remodeling in both groups of mice were similar. Gene expression analysis revealed that hyperglycemia impaired cholesterol transport by modulating ATP-binding cassette A1, ATP-binding cassette G1, scavenger receptor class B family member (CD36), scavenger receptor class B1, and wound healing pathways in lesional macrophages during atherosclerosis regression. Hyperglycemia impairs both reduction in size and loss of lipids from atherosclerotic lesions upon plasma Lipid lowering without significantly affecting the remodeling of the vascular wall.