Metformin inhibits angiotensin II-induced differentiation of cardiac fibroblasts into myofibroblasts.
Metformin inhibits angiotensin II-induced differentiation of cardiac fibroblasts into myofibroblasts.
复制标题
二甲双胍抑制血管紧张素 II 诱导的心肌成纤维细胞分化为肌成纤维细胞
DOI：
10.1371/journal.pone.0072120
复制
发表时间：
2013
期刊：
影响因子：
3.7
通讯作者：
Xu B
中科院分区：
文献类型：
--
作者：
Bai J;Zhang N;Hua Y;Wang B;Ling L;Ferro A;Xu B
心脏成纤维细胞分化为肌成纤维细胞是导致病理性心脏重塑的心脏纤维化进展中的关键事件。二甲双胍是一种抗糖尿病药，具有多种心脏保护特性。然而，关于二甲双胍对心脏成纤维细胞分化的影响知之甚少。因此，在本研究中，我们研究了二甲双胍对血管紧张素（Ang）II诱导的心肌成纤维细胞分化为肌成纤维细胞的影响及其潜在机制。在存在或不存在二甲双胍 (10–200 µM) 的情况下，用 Ang II (100 nM) 刺激成年大鼠心脏成纤维细胞。 Ang II 刺激诱导心脏成纤维细胞分化为肌成纤维细胞，α-平滑肌肌动蛋白 (α-SMA) 和 I 型和 III 型胶原表达增加表明，而用二甲双胍预处理心脏成纤维细胞可抑制 Ang II 的这种作用。二甲双胍还通过抑制 PKC-NADPH 氧化酶途径的激活，减少心脏成纤维细胞中 Ang II 诱导的活性氧 (ROS) 生成。使用 PKC 抑制剂 calphostin C 和 NADPH 氧化酶抑制剂 apocynin 进行的进一步实验证实，抑制 PKC-NADPH 氧化酶途径可显着减弱 Ang II 诱导的 ROS 生成和肌成纤维细胞分化。这些数据表明，二甲双胍通过抑制成年大鼠心脏成纤维细胞中的 PKC-NADPH 氧化酶途径来抑制 ROS 生成，从而抑制 Ang II 诱导的肌成纤维细胞分化。我们的结果提供了有关二甲双胍心脏保护作用的新机制见解，并提供了减轻心脏纤维化的有效治疗策略。
Differentiation of cardiac fibroblasts into myofibroblasts is a critical event in the progression of cardiac fibrosis that leads to pathological cardiac remodeling. Metformin, an antidiabetic agent, exhibits a number of cardioprotective properties. However, much less is known regarding the effect of metformin on cardiac fibroblast differentiation. Thus, in the present study, we examined the effect of metformin on angiotensin (Ang) II-induced differentiation of cardiac fibroblasts into myofibroblasts and its underlying mechanism. Adult rat cardiac fibroblasts were stimulated with Ang II (100 nM) in the presence or absence of metformin (10–200 µM). Ang II stimulation induced the differentiation of cardiac fibroblasts into myofibroblasts, as indicated by increased expression of α-smooth muscle actin (α-SMA) and collagen types I and III, and this effect of Ang II was inhibited by pretreatment of cardiac fibroblasts with metformin. Metformin also decreased Ang II-induced reactive oxygen species (ROS) generation in cardiac fibroblasts via inhibiting the activation of the PKC-NADPH oxidase pathway. Further experiments using PKC inhibitor calphostin C and NADPH oxidase inhibitor apocynin confirmed that inhibition of the PKC-NADPH oxidase pathway markedly attenuated Ang II-induced ROS generation and myofibroblast differentiation. These data indicate that metformin inhibits Ang II-induced myofibroblast differentiation by suppressing ROS generation via the inhibition of the PKC-NADPH oxidase pathway in adult rat cardiac fibroblasts. Our results provide new mechanistic insights regarding the cardioprotective effects of metformin and provide an efficient therapeutic strategy to attenuate cardiac fibrosis.
登录
查看更多内容
影响因子：
8.3
作者：
Petrov, VV;Fagard, RH;Lijnen, PJ
通讯作者：
Lijnen, PJ
影响因子：
7.4
作者：
Hensley, K;Robinson, KA;Floyd, RA
通讯作者：
Floyd, RA
DOI：
10.1152/ajpheart.00341.2006
发表时间：
2006-10-01
影响因子：
4.8
作者：
Chen, Jiawei;Mehta, Jawahar L.
通讯作者：
Mehta, Jawahar L.
DOI：
10.1073/pnas.0408704102
发表时间：
2005-01-11
影响因子：
11.1
作者：
Swaney, JS;Roth, DM;Insel, PA
通讯作者：
Insel, PA
影响因子：
8.3
作者：
Matsui, Y;Jia, N;Uede, T
通讯作者：
Uede, T