Anagliptin, a dipeptidyl peptidase-4 inhibitor, decreases macrophage infiltration and suppresses atherosclerosis in aortic and coronary arteries in cholesterol-fed rabbits
Anagliptin, a dipeptidyl peptidase-4 inhibitor, decreases macrophage infiltration and suppresses atherosclerosis in aortic and coronary arteries in cholesterol-fed rabbits
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DOI：
10.1016/j.metabol.2016.03.010
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发表时间：
2016-06-01
影响因子：
9.8
通讯作者：
Goto, Moritaka
中科院分区：
文献类型：
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作者：
Hirano, Tsutomu;Yamashita, Satoko;Goto, Moritaka
导论.几项研究已经证明，二肽基肽酶-4（DPP-4）抑制剂可抑制高胆固醇血症小鼠的主动脉粥样硬化。然而，DPP-4抑制剂是否也在冠状动脉中发挥抗动脉粥样硬化作用仍不清楚。我们研究了DPP-4抑制剂anagliptin对高胆固醇饮食喂养家兔主动脉和冠状动脉粥样硬化发展的影响。日本白色家兔饲喂正常饲料（n = 8）或含0.5%胆固醇的饲料（n = 34）14周。给胆固醇喂养的家兔饮用水中加入0.3%或不加入0.3%的阿格列汀（各n = 16和18），持续12周。膳食胆固醇摄入显著增加血清总胆固醇（TC）水平（1464 +/- 150 mg/dL，平均值+/- SE），在极低密度的主要脂蛋白中观察到最显著的增加。脂蛋白（VLDL），通过高效液相色谱法测定。阿格列汀给药后，未观察到体重、饮水量、血红蛋白A1 c或葡萄糖对静脉葡萄糖负荷的反应发生显著变化。阿格列汀轻微降低TC和VLDL胆固醇以及胆固醇吸收标志物谷甾醇和菜油甾醇，但不显著。通过阿格列汀治疗，血清DPP-4活性被抑制82%，活性胰高血糖素样肽-1和葡萄糖依赖性促胰岛素多肽水平增加2- 3倍。严重的高胆固醇血症导致主动脉粥样硬化的发展，动脉粥样硬化病变占主动脉总表面积的比例为22 +/-2%。阿格列汀将病变比率抑制至9 ± 2%（p < 0.001）。在冠状动脉中清楚地观察到动脉粥样硬化病变，其中平均内膜-中膜面积增大，并形成内膜。阿格列汀治疗使内膜-中层面积和内膜面积减小了43%。阿格列汀治疗后，冠状动脉中α-平滑肌肌动蛋白阳性和巨噬细胞阳性区域分别被抑制66%和75%。主动脉病变率与冠状动脉内膜面积呈显著正相关（r = 0.506，p < 0.01），各病变与TC呈显著正相关。阿格列汀治疗后，颈动脉中促炎细胞因子肿瘤坏死因子-α和白细胞介素-6的基因表达显著降低约90%，血管DPP-4活性降低66%。我们首次证明了DPP-4抑制剂可以显著抑制冠状动脉中的斑块形成，并可能通过其抗炎特性显著减少巨噬细胞积聚。(C)2016 Elsevier Inc. All rights reserved.
Introduction. Several studies have demonstrated suppression of aortic atherosclerosis by dipeptidyl peptidase-4 (DPP-4) inhibitors in hypercholesterolemic mice. However, it remains unknown whether DPP-4 inhibitors also exert anti-atherogenic effects in coronary arteries. We examined the effect of anagliptin, a DPP-4 inhibitor, on atherosclerosis development in the aorta and coronary arteries in a high-cholesterol diet-fed rabbits.Methods. Japanese white rabbits were fed either normal chow (n = 8) or a diet containing 0.5% cholesterol (n = 34) for 14 weeks. Cholesterol-fed rabbits were given 0.3% anagliptin or not in drinking water (each n = 16 and 18) for 12 weeks.Results. Dietary cholesterol intake markedly increased serum total cholesterol (TC) levels (1464 +/- 150 mg/dL, mean +/- SE), and the most striking increase was observed among the major lipoproteins in very low-density. lipoprotein (VLDL) as determined by high-performance liquid chromatography. No significant changes were observed in body weight, water intake, hemoglobin A1c, or glucose response to intravenous glucose loading following anagliptin administration. Anagliptin decreased TC and VLDL-cholesterol as well as cholesterol absorption markers sitosterol and campesterol slightly, although not significantly. Serum DPP-4 activity was suppressed by 82%, and active glucagon-like peptide-1 and glucose-dependent insulinotropic polypeptide levels were increased 2- to 3-fold by anagliptin treatment. Severe hypercholesterolemia resulted in the development of atherosclerosis in the aorta, and the ratio of atherosclerotic lesions to the total aortic surface area was 22 +/- 2%. Anagliptin suppressed the lesion ratio to 9 +/- 2% (p < 0.001). Atherosclerotic lesions were clearly observed in the coronary arteries, where the mean intima-media area was enlarged, and intimal formation was developed. Anagliptin treatment attenuated the intima-media area and the intimal area by 43%. Alpha-smooth muscle actin-positive and macrophage-positive areas in the coronary arteries were suppressed by 66 and 75%, respectively, after anagliptin treatment. The aortic lesion ratio and the coronary intima area were correlated with each other (r = 0.506, p < 0.01), and each lesion correlated with TC in the whole cholesterol-fed rabbits. Gene expression of the proinflammatory cytokines tumor necrosis factor-alpha and interleukin-6 in the carotid arteries was markedly reduced by approximately 90%, and vascular DPP-4 activity was reduced by 66% after anagliptin treatment.Conclusions. We demonstrated for the first time that a DPP-4 inhibitor can substantially suppress plaque formation in coronary arteries with a marked reduction in macrophage accumulation likely via its anti-inflammatory properties. (C) 2016 Elsevier Inc. All rights reserved.