Institute of Health Research-INCLIVA, Avda Menéndez Pelayo 4, 46010, Valencia, Spain.
Clinic Hospital and Department of Medicine, University of Valencia, Institute of Health Research-INCLIVA, Valencia, Spain.
Diabetologia. 2017 Sep;60(9):1801-1812. doi: 10.1007/s00125-017-4330-3. Epub 2017 Jun 12.
AIMS/HYPOTHESIS: Recent clinical studies indicate that glucagon-like peptide-1 (GLP-1) analogues prevent acute cardiovascular events in type 2 diabetes mellitus but their mechanisms remain unknown. In the present study, the impact of GLP-1 analogues and their potential underlying molecular mechanisms in insulin resistance and atherosclerosis are investigated.
Atherosclerosis development was evaluated in Apoe Irs2 mice, a mouse model of insulin resistance, the metabolic syndrome and atherosclerosis, treated with the GLP-1 analogues lixisenatide or liraglutide. In addition, studies in Apoe Irs2 mice and mouse-derived macrophages treated with lixisenatide were performed to investigate the potential inflammatory intracellular pathways.
Treatment of Apoe Irs2 mice with either lixisenatide or liraglutide improved glucose metabolism and blood pressure but this was independent of body weight loss. Both drugs significantly decreased atheroma plaque size. Compared with vehicle-treated control mice, lixisenatide treatment generated more stable atheromas, with fewer inflammatory infiltrates, reduced necrotic cores and thicker fibrous caps. Lixisenatide-treated mice also displayed diminished IL-6 levels, proinflammatory Ly6C monocytes and activated T cells. In vitro analysis showed that, in macrophages from Apoe Irs2 mice, lixisenatide reduced the secretion of the proinflammatory cytokine IL-6 accompanied by enhanced activation of signal transducer and activator of transcription (STAT) 3, which is a determinant for M2 macrophage differentiation. STAT1 activation, which is essential for M1 phenotype, was also diminished. Furthermore, atheromas from lixisenatide-treated mice showed higher arginase I content and decreased expression of inducible nitric oxide synthase, indicating the prevalence of the M2 phenotype within plaques.
CONCLUSIONS/INTERPRETATION: Lixisenatide decreases atheroma plaque size and instability in Apoe Irs2 mice by reprogramming macrophages towards an M2 phenotype, which leads to reduced inflammation. This study identifies a critical role for this drug in macrophage polarisation inside plaques and provides experimental evidence supporting a novel mechanism of action for GLP-1 analogues in the reduction of cardiovascular risk associated with insulin resistance.
目的/假设：最近的临床研究表明，胰高血糖素样肽-1（GLP-1）类似物可预防 2 型糖尿病患者的急性心血管事件，但它们的机制尚不清楚。本研究旨在探讨 GLP-1 类似物及其在胰岛素抵抗和动脉粥样硬化中的潜在分子机制。
在载脂蛋白 E（Apoe）Irs2 小鼠（胰岛素抵抗、代谢综合征和动脉粥样硬化的小鼠模型）中评估动脉粥样硬化的发展，并用 GLP-1 类似物利西那肽或利拉鲁肽进行治疗。此外，还在 Apoe Irs2 小鼠和用利西那肽处理的小鼠源性巨噬细胞中进行了研究，以探讨潜在的炎症细胞内途径。
用利西那肽或利拉鲁肽治疗 Apoe Irs2 小鼠可改善葡萄糖代谢和血压，但与体重减轻无关。两种药物均显著减少动脉粥样硬化斑块的大小。与用载体处理的对照组小鼠相比，利西那肽治疗产生了更稳定的动脉粥样硬化斑块，炎症浸润减少，坏死核心减少，纤维帽增厚。利西那肽治疗的小鼠还显示出较低的白细胞介素 6（IL-6）水平、促炎 Ly6C 单核细胞和活化 T 细胞。体外分析表明，在 Apoe Irs2 小鼠的巨噬细胞中，利西那肽可减少促炎细胞因子 IL-6 的分泌，并增强信号转导和转录激活因子（STAT）3 的激活，后者是 M2 巨噬细胞分化的决定因素。对于 M1 表型至关重要的 STAT1 激活也减少。此外，利西那肽治疗的小鼠的动脉粥样硬化斑块中精氨酸酶 I 的含量较高，诱导型一氧化氮合酶的表达降低，表明斑块内存在 M2 表型。
结论/解释：利西那肽通过将巨噬细胞重编程为 M2 表型来减少 Apoe Irs2 小鼠的动脉粥样硬化斑块大小和不稳定性，从而减少炎症。这项研究确定了该药物在斑块内巨噬细胞极化中的关键作用，并提供了支持 GLP-1 类似物通过降低与胰岛素抵抗相关的心血管风险的新型作用机制的实验证据。
