Bułdak Łukasz, Łabuzek Krzysztof, Bułdak Rafał Jakub, Machnik Grzegorz, Bołdys Aleksandra, Okopień Bogusław
Department of Internal Medicine and Clinical Pharmacology, School of Medicine in Katowice, Medical University of Silesia, Medykow 18, 40-752, Katowice, Poland,
Naunyn Schmiedebergs Arch Pharmacol. 2015 Sep;388(9):905-19. doi: 10.1007/s00210-015-1124-3. Epub 2015 May 19.
Macrophages are dominant cells in the pathogenesis of atherosclerosis. They are also a major source of reactive oxygen species (ROS). Oxidative stress, which is particularly high in subjects with diabetes, is responsible for accelerated atherosclerosis. Novel antidiabetic drugs (e.g., glucagon-like peptide-1 (GLP-1) agonists) were shown to reduce ROS level. Therefore, we conceived a study to evaluate the influence of exenatide, a GLP-1 agonist, on redox status in human monocytes/macrophages cultured in vitro, which may explain the beneficial effects of incretin-based antidiabetic treatment. Human macrophages obtained from 10 healthy volunteers were in vitro subjected to the treatment with GLP-1 agonist (exenatide) in the presence of lipopolysaccharide (LPS), antagonist of GLP-1 receptors (exendin 9-39), or protein kinase A inhibitor (H89). Afterwards, reactive oxygen species, malondialdehyde level, NADPH oxidase, and antioxidative enzymes [superoxide dismutase (SOD), glutathione peroxidase (GSH-Px), and catalase] expression was evaluated. Finally, we estimated the activity of the abovementioned enzymes in the presence of H89. According to our findings, exenatide reduced ROS and malondialdyhyde (MDA) level by decreasing the expression of ROS-generating NADPH oxidase and by increasing the expression and activities of SOD and GSH-Px. We also showed that this effect was significantly inhibited by exendin 9-39 (a GLP-1 antagonist) and blocked by H89. Exenatide improved the antioxidative potential and reduced oxidative stress in cultured human monocytes/macrophages, and this finding may be responsible for the pleiotropic effects of incretin-based therapies. This effect relied on the stimulation of GLP-1 receptor.
巨噬细胞是动脉粥样硬化发病机制中的主要细胞。它们也是活性氧（ROS）的主要来源。氧化应激在糖尿病患者中尤其高，是加速动脉粥样硬化的原因。新型抗糖尿病药物（如胰高血糖素样肽-1（GLP-1）激动剂）已显示可降低ROS水平。因此，我们构思了一项研究，以评估GLP-1激动剂艾塞那肽对体外培养的人单核细胞/巨噬细胞氧化还原状态的影响，这可能解释了基于肠促胰岛素的抗糖尿病治疗的有益效果。从10名健康志愿者获得的人巨噬细胞在体外接受GLP-1激动剂（艾塞那肽）处理，同时存在脂多糖（LPS）、GLP-1受体拮抗剂（艾塞那肽9-39）或蛋白激酶A抑制剂（H89）。之后，评估活性氧、丙二醛水平、NADPH氧化酶和抗氧化酶[超氧化物歧化酶（SOD）、谷胱甘肽过氧化物酶（GSH-Px）和过氧化氢酶]的表达。最后，我们在H89存在的情况下估计上述酶的活性。根据我们的发现，艾塞那肽通过降低产生ROS的NADPH氧化酶的表达以及增加SOD和GSH-Px的表达和活性来降低ROS和丙二醛（MDA）水平。我们还表明，这种作用被艾塞那肽9-39（一种GLP-1拮抗剂）显著抑制，并被H89阻断。艾塞那肽改善了体外培养的人单核细胞/巨噬细胞的抗氧化潜力并降低了氧化应激，这一发现可能是基于肠促胰岛素疗法的多效性作用的原因。这种作用依赖于GLP-1受体的刺激。
