Pharmacological Inhibition of Focal Adhesion Kinase Attenuates Cardiac Fibrosis in Mice Cardiac Fibroblast and Post-Myocardial-Infarction Models
Pharmacological Inhibition of Focal Adhesion Kinase Attenuates Cardiac Fibrosis in Mice Cardiac Fibroblast and Post-Myocardial-Infarction Models
复制标题
局灶粘附激酶的药理学抑制可减轻小鼠心脏成纤维细胞和心肌梗死后模型中的心脏纤维化。
DOI：
10.1159/000430373
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发表时间：
2015-01-01
影响因子：
--
通讯作者：
Wang, Xu
中科院分区：
文献类型：
--
作者：
Fan, Guang-Pu;Wang, Wei;Wang, Xu
背景：探讨局灶黏附激酶（FAK）介导的信号在小鼠缺氧诱导的心肌成纤维细胞（CFs）分化和心肌梗死后（MI）心肌纤维化中的作用。方法：在常氧、缺氧或缺氧+PP2（一种Src激酶家族抑制剂）条件下处理新生C57BL/6小鼠的CFs。采用RT-PCR和免疫荧光染色分别检测FAK、α -平滑肌肌动蛋白（α - sma）和I型胶原α 1 （Col1 α 1）基因表达水平，以及α - sma和波形蛋白水平。30只小鼠手术分为假手术组（n=7）和心肌梗死组（n=23）；FAK抑制剂PF-562271给予6只MI存活小鼠（PF组，来自15只存活小鼠）。超声心动图、马森三色法和天狼星红染色法分别检测心脏功能和胶原组织。分析I型胶原蛋白、FAK蛋白、mTOR、ERK1/2、AKT、P70S6K和phospho-FAK水平。结果：缺氧条件下，PP2对FAK的抑制作用可显著降低CFs的分化和胶原合成。在体内，PF-562271治疗导致纤维化衰减；然而，心肌梗死小鼠恶化的心功能没有明显改善。PF-562271可能影响磷- tor (p
Background: To investigate the role of focal adhesion kinase (FAK)-mediated signaling in hypoxia-induced cardiac fibroblasts (CFs) differentiation and cardiac fibrosis post-myocardial infarction (MI) on a mice model. Methods: CFs of neonatal C57BL/6 mice were treated under normoxic, hypoxic, or hypoxic+PP2 (known as a Src kinase family inhibitor) conditions. Gene expressions of FAK, alpha-smooth muscle actin (alpha-SMA) and collagen type I alpha 1 (Col1 alpha 1), or alpha-SMA and vimentin levels were performed by RT-PCR and immunofluorescence staining, respectively. Thirty mice were surgically treated into Sham (n=7) and MI (n=23) groups; and FAK inhibitor PF-562271 was given to six survivor MI mice (as PF group, from 15 survivors). Heart function and collagenous tissues were examined by echocardiography, as well as by Masson's trichrome and Sirius red staining, respectively. Type I collagen, FAK protein, mTOR, ERK1/2, AKT, P70S6K and phospho-FAK levels were also analyzed. Results: FAK inhibition with PP2 significantly decreased CFs differentiation and collagen synthesis under hypoxia treatment. In vivo, PF-562271 treatment resulted in fibrosis attenuation; however, deteriorated heart function of MI mice could not be significantly improved. PF-562271 may affect phosphom-TOR (p