Anti-atherogenic and anti-inflammatory properties of glucagon-like peptide-1, glucose-dependent insulinotropic polypepide, and dipeptidyl peptidase-4 inhibitors in experimental animals.
Anti-atherogenic and anti-inflammatory properties of glucagon-like peptide-1, glucose-dependent insulinotropic polypepide, and dipeptidyl peptidase-4 inhibitors in experimental animals.
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DOI：
10.1111/jdi.12446
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发表时间：
2016-04
影响因子：
3.2
通讯作者：
Mori Y
中科院分区：
文献类型：
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作者：
Hirano T;Mori Y
我们报告了天然肠促胰岛素、利拉鲁肽和二肽基肽酶-4抑制剂（DPP-4 i）均在载脂蛋白E-null（Apoe −/−）小鼠中具有抗动脉粥样硬化作用。我们在小鼠导丝损伤模型中证实了肠促胰岛素相关药物的抗动脉粥样硬化特性，其中股动脉中的新生内膜形成受到显著抑制。此外，我们发现DPP-4 i可显著抑制冠状动脉斑块形成，并显著减少胆固醇喂养家兔中巨噬细胞的蓄积。DPP-4 i主要通过胰高血糖素样肽-1和葡萄糖依赖性促胰岛素多肽的作用在Apoe −/−小鼠中显示出抗动脉粥样硬化作用。然而，双重肠促胰岛素受体拮抗剂部分减弱了DPP-4 i对糖尿病Apoe −/−小鼠动脉粥样硬化的抑制作用，表明其机制不依赖于肠促胰岛素。Exendin-4和葡萄糖依赖性促胰岛素多肽引起环磷酸腺苷生成，并抑制U937人单核细胞中脂多糖诱导的炎症分子（如白细胞介素-1 β、白细胞介素-6和肿瘤坏死因子-α）的基因表达。然而，这种抑制作用被腺苷酸环化酶抑制剂减弱，并被8-溴环腺苷酸或毛喉素模拟。DPP-4 i显著抑制脂多糖诱导的炎性细胞因子表达，而不影响环磷酸腺苷生成或细胞增殖。DPP-4 i比肠促胰岛素更强烈地抑制脂多糖诱导的炎症分子基因表达，最可能通过灭活CD 26。胰高血糖素样肽-1和葡萄糖依赖性促胰岛素多肽以受体依赖性方式抑制氧化低密度脂蛋白诱导的巨噬细胞泡沫细胞形成，这与酰基辅酶A胆固醇酰基转移酶-1和CD 36的下调以及三磷酸腺苷结合盒转运蛋白A1的上调有关。我们的研究强烈表明，肠促胰岛素相关药物对实验动物中巨噬细胞驱动的动脉粥样硬化具有有利作用。
We reported that native incretins, liraglutide and dipeptidyl peptidase‐4 inhibitors (DPP‐4i) all confer an anti‐atherosclerotic effect in apolipoprotein E‐null (Apoe −/−) mice. We confirmed the anti‐atherogenic property of incretin‐related agents in the mouse wire injury model, in which the neointimal formation in the femoral artery is remarkably suppressed. Furthermore, we showed that DPP‐4i substantially suppresses plaque formation in coronary arteries with a marked reduction in the accumulation of macrophages in cholesterol‐fed rabbits. DPP‐4i showed an anti‐atherosclerotic effect in Apoe −/− mice mainly through the actions of glucagon‐like peptide‐1 and glucose‐dependent insulinotropic polypepide. However, the dual incretin receptor antagonists partially attenuated the suppressive effect of DPP‐4i on atherosclerosis in diabetic Apoe −/− mice, suggesting an incretin‐independent mechanism. Exendin‐4 and glucose‐dependent insulinotropic polypepide elicited cyclic adenosine monophosphate generation, and suppressed the lipopolysaccharide‐induced gene expression of inflammatory molecules, such as interleukin‐1β, interleukin‐6 and tumor necrosis factor‐α, in U937 human monocytes. This suppressive effect, however, was attenuated by an inhibitor of adenylate cyclase and mimicked by 8‐bromo‐cyclic adenosine monophosphate or forskolin. DPP‐4i substantially suppressed the lipopolysaccharide‐induced expression of inflammatory cytokines without affecting cyclic adenosine monophosphate generation or cell proliferation. DPP‐4i more strongly suppressed the lipopolysaccharide‐induced gene expression of inflammatory molecules than incretins, most likely through inactivation of CD26. Glucagon‐like peptide‐1 and glucose‐dependent insulinotropic polypepide suppressed oxidized low‐density lipoprotein‐induced macrophage foam cell formation in a receptor‐dependent manner, which was associated with the downregulation of acyl‐coenzyme A cholesterol acyltransferase‐1 and CD36, as well as the up‐regulation of adenosine triphosphate‐binding cassette transporter A1. Our studies strongly suggest that incretin‐related agents have favorable effects on macrophage‐driven atherosclerosis in experimental animals.