Wang Xianwei, Ding Zufeng, Yang Fen, Dai Yao, Chen Peng, Theus Sue, Singh Sharda, Budhiraja Madhu, Mehta Jawahar L
Central Arkansas Veterans Healthcare System, and the Division of Cardiology, University of Arkansas for Medical Sciences, Little Rock, AR, U.S.A. Henan Key Laboratory of Medical Tissue Regeneration, Xinxiang Medical University, Xinxiang, Henan, China.
Central Arkansas Veterans Healthcare System, and the Division of Cardiology, University of Arkansas for Medical Sciences, Little Rock, AR, U.S.A.
Clin Sci (Lond). 2016 Aug 1;130(15):1353-62. doi: 10.1042/CS20160061. Epub 2016 Apr 26.
Studies have indicated that dipeptidyl peptidase-4 (DPP-4) inhibitors and glucagon-like peptide-1 (GLP-1) agonists reduce infarct size after myocardial ischaemia. Whether these agents modify cardiac remodelling after ischaemia is unclear. Furthermore, it is not known if combination of the two types of drugs is superior to either agent alone. We investigated the modulatory effect of the DPP-4 inhibitor linagliptin alone, the GLP-1 activator liraglutide alone, or the two agents together on myocardial infarct size, left ventricular contractile function and cardiac remodelling signals after a brief period of left coronary artery (LCA) occlusion. C57BL/6 mice were treated with vehicle, the DPP-4 inhibitor linagliptin, the GLP-1 activator liraglutide, or both agents together for 5 days, and then subjected to LCA occlusion (1 h) and reperfusion (3 h). Ischaemia-reperfusion increased reactive oxygen species (ROS) generation and expression of NADPH oxidase (p47(phox), p22(phox) and gp91(phox) subtypes), collagens, fibronectin and proinflammatory cytokines (interleukin 6, tumour necrosis factor α and monocyte chemoattractant protein-1) in the LCA-supplied regions. Pre-treatment with linagliptin or liraglutide reduced infarct size, protected cardiomyocytes from injury and preserved cardiac contractile function in a similar fashion. It is interesting that profibrotic (collagen deposition) signals were expressed soon after ischaemia-reperfusion. Both linagliptin and liraglutide suppressed ROS generation, NADPH oxidase and proinflammatory signals, and reduced collagen deposition. Addition of linagliptin or liraglutide had no significant additive effect above and beyond that of liraglutide and linagliptin given alone. In conclusion, linagliptin and liraglutide can improve cardiac contractile function and indices of cardiac remodelling, which may be related to their role in inhibition of ROS production and proinflammatory cytokines after ischaemia.
研究表明，二肽基肽酶-4（DPP-4）抑制剂和胰高血糖素样肽-1（GLP-1）激动剂可减小心肌缺血后的梗死面积。这些药物是否能改变缺血后的心脏重塑尚不清楚。此外，两种药物联合使用是否优于单独使用其中任何一种药物也未知。我们研究了单独使用DPP-4抑制剂利格列汀、单独使用GLP-1激动剂利拉鲁肽或两者联合使用对短暂左冠状动脉（LCA）闭塞后心肌梗死面积、左心室收缩功能和心脏重塑信号的调节作用。将C57BL/6小鼠用溶剂、DPP-4抑制剂利格列汀、GLP-1激动剂利拉鲁肽或两种药物联合处理5天，然后进行LCA闭塞（1小时）和再灌注（3小时）。缺血再灌注增加了LCA供血区域的活性氧（ROS）生成以及NADPH氧化酶（p47(phox)、p22(phox)和gp91(phox)亚型）、胶原蛋白、纤连蛋白和促炎细胞因子（白细胞介素6、肿瘤坏死因子α和单核细胞趋化蛋白-1）的表达。利格列汀或利拉鲁肽预处理以相似的方式减小了梗死面积，保护心肌细胞免受损伤并保留了心脏收缩功能。有趣的是，缺血再灌注后很快就表达了促纤维化（胶原蛋白沉积）信号。利格列汀和利拉鲁肽均抑制了ROS生成、NADPH氧化酶和促炎信号，并减少了胶原蛋白沉积。添加利格列汀或利拉鲁肽并没有比单独给予利拉鲁肽和利格列汀产生更显著的叠加效应。总之，利格列汀和利拉鲁肽可改善心脏收缩功能和心脏重塑指标，这可能与其在缺血后抑制ROS产生和促炎细胞因子的作用有关。
