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Effects of linagliptin and liraglutide on glucose- and angiotensin Ⅱ-induced collagen formation and cytoskeleton degradation in cardiac fibroblasts in vitro

Effects of linagliptin and liraglutide on glucose- and angiotensin Ⅱ-induced collagen formation and cytoskeleton degradation in cardiac fibroblasts in vitro
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摘要 瞄准:象 Glucagon 一样 peptide-1 (GLP-1 ) 收缩筋和 dipeptidyl peptidase-4 (DPP-4 ) 禁止者不能仅仅降低血葡萄糖层次,而且减轻在心肌的局部缺血和高血压以后的心脏的改变。在现在的学习,我们在葡萄糖上调查了一个 DPP-4 禁止者(linagliptin ) 和 GLP-1 使活跃之物(liraglutide ) 的效果 -- 并且血管收缩素 II (Ang II ) 在 vitro 在心脏的成纤维细胞导致了骨胶原形成和细胞骨架重组,并且阐明相关 mechanisms.Methods:心脏的成纤维细胞从 6-week-old C57BL/6 老鼠的心被孤立,然后为 24 h 暴露了到葡萄糖或 Ang II 的不同集中。fibrotic 的表达式发信号(象 ERK1/2 和 NF-&#x003BA 一样的 fibronectin, collagen-1, -3 和 -4), ;在成纤维细胞的 B-p65 用西方的弄污被检验试金。F 肌动朊降级在在成纤维细胞的共焦的显微镜与玫瑰精 phalloidin.Results 染色了的转换激光下面被检测:葡萄糖(1-40 mmol/L ) 和 Ang II (10 <sup>&#x02212;8</sup>-10<sup>&#x02212;5</sup> mol/L ) dose-dependently 增加了 fibronectin,骨胶原, phospho-ERK1/2 和 phospho-NF-&#x003BA 的表示;在心脏的成纤维细胞的 B-p65。葡萄糖的高集中(&#x02265; 40 mmol/L ) 并且 Ang II (&#x02265; 10 <sup>&#x02212;6</sup> mol/L ) 引起了 F 肌动朊(更少的集会 F 肌动朊纤维和更多拆卸纤维) 的重要降级。ERK1/2 禁止者 U0126 (10 &#x003BC; mol/L ) 并且 NF-&#x003BA; B 禁止者 JSH-23 (10 &#x003BC; mol/L ) 两个显著地压制了葡萄糖 -- 并且血管收缩素在心脏的成纤维细胞的导致 II 的 fibronectin 和骨胶原表情。而且,有 liraglutide (10-100 nmol/L ) 的预告的处理或 linagliptin (3 和 30 nmol/L ) 显著地减少了葡萄糖 -- 并且 fibrotic 信号, phospho-ERK1/2 和 phospho-NF-&#x003BA 的 Ang 导致 II 的表示;在心脏的成纤维细胞的 B-p65。而且,然而,有 liraglutide (30 nmol/L ) 的预告的处理或 liraglutide (100 nmol/L ) 显著地禁止了导致葡萄糖的 F 肌动 Aim: Glucagon-like peptide-1 (GLP-1) agonists and dipeptidyl peptidase-4 (DPP-4) inhibitors can not only lower blood glucose levels, but also alleviate cardiac remodeling after myocardial ischemia and hypertension. In the present study, we investigated the effects of a DPP-4 inhibitor (linagliptin) and a GLP-1 activator (liraglutide) on glucose- and angiotensin Ⅱ (Ang Ⅱ)-induced collagen formation and cytoskeleton reorganization in cardiac fibroblasts in vitro, and elucidated the related mechanisms. Methods: Cardiac fibroblasts were isolated from the hearts of 6-week-old C57BL/6 mice, and then exposed to different concentrations of glucose or Ang Ⅱ for 24 h. The expression of fibrotic signals (fibronectin, collagen-1, -3 and -4), as well as ERK1/2 and NF-KB-p65 in the fibroblasts was examined using Western blotting assays. F-actin degradation was detected under inverted laser confocal microscope in fibroblasts stained with Rhodamine phalloidin.Results: Glucose (1-40 mmol/L) and Ang Ⅱ (10-8-10-5 mol/L) dose-dependently increased the expression of fibronectin, collagens, phosphoERK1/2 and phospho-NF-KB-p65 in cardiac fibroblasts. High concentrations of glucose (〉40 mmol/L) and Ang Ⅱ (≥10-6 mol/L) caused a significant degradation of F-actin (less assembly F-actin fibers and more disassembly fibers). ERK1/2 inhibitor U0126 (10 μmol/L) and NF-κB inhibitor JSH-23 (10 μmol/L) both markedly suppressed glucose- and angiotensin Ⅱ-induced fibronectin and collagen expressions in cardiac fibroblasts. Furthermore, pretreatment with liraglutide (10-100 nmol/L) or linagliptin (3 and 30 nmol/L) significantly decreased glucose- and Ang Ⅱ-induced expression of fibrotic signals, phospho-ERK1/2 and phospho-NF-κB-p65 in cardiac fibroblasts. Moreover, pretreatment with liraglutide (30 nmol/L) or liraglutide (100 nmol/L) markedly inhibited glucose-induced F-actin degradation, however, only liraglutide inhibited Ang κ-induced F-actin degrada
作者 Xian-wei WANG Fen-xi ZHANG Fen YANG Zu-feng DING Nidhi AGARWAL Zhi-kun GUO Jawahar L MEHTA Wang, Xian-wei[1,2,3];Zhang, Fen-xi[4];Yang, Fen[1];Ding, Zu-feng[2,3];Agarwal, Nidhi[2,3];Guo, Zhi-kun[1];Mehta, Jawahar L.[2,3];
出处 《中国药理学报:英文版》 SCIE CAS CSCD 2016年第10期1349-1358,共10页 Acta Pharmacologica Sinica
基金 Acknowledgements This study was supported by grants from the Department of Veterans Affairs, Veterans Health Administration, Office of Research and Development, Biomedical Laboratory Research and Development (Washington, DC, USA) (grant No BX-000282-05), the National Natural Science Foundation of China (grant No 81370428 and 31401246) and Boehringer Ingelheim Pharmaceuticals, Inc (Ridgefield, CT, USA).
关键词 心脏的改变 心脏的成纤维细胞 葡萄糖 血管收缩素 II 骨胶原形成 细胞骨架组织 LINAGLIPTIN LIRAGLUTIDE cardiac remodeling cardiac fibroblast glucose angiotensin Ⅱ collagen formation cytoskeleton organization linagliptin liraglutide
作者简介 E-mail xwang2@uams.edu
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参考文献33

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