Apolipoprotein AI) Promotes Atherosclerosis Regression in Diabetic Mice by Suppressing Myelopoiesis and Plaque Inflammation
Apolipoprotein AI) Promotes Atherosclerosis Regression in Diabetic Mice by Suppressing Myelopoiesis and Plaque Inflammation
复制标题
载脂蛋白AI通过抑制髓系造血及斑块炎症促进糖尿病小鼠动脉粥样硬化的消退
DOI：
10.1161/circulationaha.119.039476
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发表时间：
2019-10-01
期刊：
影响因子：
37.8
通讯作者：
Fisher, Edward A.
中科院分区：
文献类型：
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作者：
Barrett, Tessa J.;Distel, Emilie;Fisher, Edward A.
背景：尽管胆固醇显著降低，但糖尿病患者的心血管疾病风险仍然增加。与此一致，糖尿病损害了人类和小鼠降低胆固醇后的动脉粥样硬化消退。在小鼠中，这部分归因于高血糖诱导的单核细胞增多症，尽管胆固醇降低，但单核细胞进入斑块的数量增加。此外，糖尿病使斑块巨噬细胞倾向于致动脉粥样硬化的炎性M1表型，而不是倾向于降低胆固醇的典型的动脉粥样硬化消退M2状态。功能性高密度脂蛋白（HDL）在糖尿病患者中通常较低，可减少小鼠骨髓中单核细胞前体增殖，并对人和小鼠巨噬细胞具有抗炎作用。我们的研究旨在测试在降低胆固醇后，提高糖尿病小鼠的功能性HDL水平是否可以预防单核细胞增多症，减少斑块巨噬细胞的数量和炎症，并增强动脉粥样硬化消退。研究方法：将Ldlr（-/-）小鼠中产生的含有斑块的主动脉弓移植到野生型、糖尿病野生型或人载脂蛋白AI转基因的糖尿病小鼠中，这些小鼠具有升高的功能性HDL。所有的小鼠都有低水平的低密度脂蛋白胆固醇，以促进斑块消退。2周后，检查受体小鼠主动脉移植物中的斑块。结果：糖尿病野生型小鼠动脉粥样硬化消退受损，通过升高HDL水平使其正常化。这种益处与抑制高血糖驱动的骨髓生成、单核细胞增多和嗜中性粒细胞增多有关。高密度脂蛋白增加改善骨髓祖细胞的胆固醇流出，抑制其增殖和单核细胞和中性粒细胞的生产能力。在糖尿病环境中，除了减少可募集到斑块中的循环单核细胞外，HDL还抑制单核细胞向炎症部位的一般募集能力，并促进斑块巨噬细胞极化至M2，即动脉粥样硬化消退状态。斑块中性粒细胞胞外陷阱也减少，这是动脉粥样硬化和糖尿病增加。结论：提高载脂蛋白AI和HDL的功能水平促进单核细胞和中性粒细胞的产生以及降低胆固醇后糖尿病小鼠动脉粥样硬化斑块的炎症环境的多种有利变化，并可能代表降低糖尿病患者心血管疾病风险的新方法。
Background: Despite robust cholesterol lowering, cardiovascular disease risk remains increased in patients with diabetes mellitus. Consistent with this, diabetes mellitus impairs atherosclerosis regression after cholesterol lowering in humans and mice. In mice, this is attributed in part to hyperglycemia-induced monocytosis, which increases monocyte entry into plaques despite cholesterol lowering. In addition, diabetes mellitus skews plaque macrophages toward an atherogenic inflammatory M1 phenotype instead of toward the atherosclerosis-resolving M2 state typical with cholesterol lowering. Functional high-density lipoprotein (HDL), typically low in patients with diabetes mellitus, reduces monocyte precursor proliferation in murine bone marrow and has anti-inflammatory effects on human and murine macrophages. Our study aimed to test whether raising functional HDL levels in diabetic mice prevents monocytosis, reduces the quantity and inflammation of plaque macrophages, and enhances atherosclerosis regression after cholesterol lowering. Methods: Aortic arches containing plaques developed in Ldlr(-/-) mice were transplanted into either wild-type, diabetic wild-type, or diabetic mice transgenic for human apolipoprotein AI, which have elevated functional HDL. Recipient mice all had low levels of low-density lipoprotein cholesterol to promote plaque regression. After 2 weeks, plaques in recipient mouse aortic grafts were examined. Results: Diabetic wild-type mice had impaired atherosclerosis regression, which was normalized by raising HDL levels. This benefit was linked to suppressed hyperglycemia-driven myelopoiesis, monocytosis, and neutrophilia. Increased HDL improved cholesterol efflux from bone marrow progenitors, suppressing their proliferation and monocyte and neutrophil production capacity. In addition to reducing circulating monocytes available for recruitment into plaques, in the diabetic milieu, HDL suppressed the general recruitability of monocytes to inflammatory sites and promoted plaque macrophage polarization to the M2, atherosclerosis-resolving state. There was also a decrease in plaque neutrophil extracellular traps, which are atherogenic and increased by diabetes mellitus. Conclusions: Raising apolipoprotein AI and functional levels of HDL promotes multiple favorable changes in the production of monocytes and neutrophils and in the inflammatory environment of atherosclerotic plaques of diabetic mice after cholesterol lowering and may represent a novel approach to reduce cardiovascular disease risk in people with diabetes mellitus.