Hypoxia-Inducible Factor Prolyl 4-Hydroxylase-2 Inhibition Protects Against Development of Atherosclerosis
Hypoxia-Inducible Factor Prolyl 4-Hydroxylase-2 Inhibition Protects Against Development of Atherosclerosis
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DOI：
10.1161/atvbaha.115.307136
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发表时间：
2016-04-01
影响因子：
8.7
通讯作者：
Koivunen, Peppi
中科院分区：
文献类型：
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作者：
Rahtu-Korpela, Lea;Maatta, Jenni;Koivunen, Peppi
目的探讨小分子缺氧诱导因子脯氨酰4-羟化酶（HIF-P4 H）抑制剂治疗贫血的临床研究。HIF-P4 H-2（也称为PHD 2或EglN 1）抑制可改善葡萄糖和脂质代谢，并防止肥胖和代谢功能障碍。我们在这里研究了HIF-P4 H-2抑制是否也可以防止atherosclerosis.Approach和Results动脉粥样硬化的发展进行了研究，在低密度脂蛋白（LDL）受体缺陷小鼠与口服HIF-P4 H抑制剂，FG-4497，并在HIF-P4 H-2-hypomorphic/C699 Y-LDL受体突变小鼠，所有小鼠被喂食高脂饮食。与溶剂给药对照组相比，LDL受体缺陷小鼠接受FG-4497给药后动脉粥样硬化斑块面积减少约50%，还降低了其体重增加、胰岛素抵抗、肝脏和白色脂肪组织（WAT）重量、脂肪细胞大小、炎症相关WAT巨噬细胞聚集体数量以及高脂饮食诱导的血清胆固醇水平升高。抗铜氧化低密度脂蛋白的动脉粥样硬化保护循环自身抗体水平增加。动脉粥样硬化斑块面积的减少与体重、血清胆固醇水平、WAT巨噬细胞聚集体和自身抗体增加的减少相关。FG-4497处理稳定了HIF-1和HIF-2，并改变了肝脏和WAT中葡萄糖和脂质代谢以及炎症相关基因的表达。HIF-P4 H-2-hypomorphic/C699 Y-LDL受体突变小鼠同样有大约50%的减少动脉粥样硬化斑块面积，减少WAT巨噬细胞聚集体的数量，并增加对氧化LDL的自身抗体，但没有降低血清胆固醇level.Conclusions HIF-P4 H-2抑制可能是一种新的策略，为防止动脉粥样硬化的发展。其机制涉及对血脂谱和先天免疫系统的有益调节以及减少炎症。
Objective Small-molecule hypoxia-inducible factor prolyl 4-hydroxylase (HIF-P4H) inhibitors are being explored in clinical studies for the treatment of anemia. HIF-P4H-2 (also known as PHD2 or EglN1) inhibition improves glucose and lipid metabolism and protects against obesity and metabolic dysfunction. We studied here whether HIF-P4H-2 inhibition could also protect against atherosclerosis.Approach and Results Atherosclerosis development was studied in low-density lipoprotein (LDL) receptor-deficient mice treated with an oral HIF-P4H inhibitor, FG-4497, and in HIF-P4H-2-hypomorphic/C699Y-LDL receptor-mutant mice, all mice being fed a high-fat diet. FG-4497 administration to LDL receptor-deficient mice reduced the area of atherosclerotic plaques by approximate to 50% when compared with vehicle-treated controls and also reduced their weight gain, insulin resistance, liver and white adipose tissue (WAT) weights, adipocyte size, number of inflammation-associated WAT macrophage aggregates and the high-fat diet-induced increases in serum cholesterol levels. The levels of atherosclerosis-protecting circulating autoantibodies against copper-oxidized LDL were increased. The decrease in atherosclerotic plaque areas correlated with the reductions in weight, serum cholesterol levels, and WAT macrophage aggregates and the autoantibody increase. FG-4497 treatment stabilized HIF-1 and HIF-2 and altered the expression of glucose and lipid metabolism and inflammation-associated genes in liver and WAT. The HIF-P4H-2-hypomorphic/C699Y-LDL receptor-mutant mice likewise had a approximate to 50% reduction in atherosclerotic plaque areas, reduced WAT macrophage aggregate numbers, and increased autoantibodies against oxidized LDL, but did not have reduced serum cholesterol levels.Conclusions HIF-P4H-2 inhibition may be a novel strategy for protecting against the development of atherosclerosis. The mechanisms involve beneficial modulation of the serum lipid profile and innate immune system and reduced inflammation.