Attenuation of endoplasmic reticulum stress using the chemical chaperone 4-phenylbutyric acid prevents cardiac fibrosis induced by isoproterenol
Attenuation of endoplasmic reticulum stress using the chemical chaperone 4-phenylbutyric acid prevents cardiac fibrosis induced by isoproterenol
复制标题
DOI：
10.1016/j.yexmp.2011.10.012
复制
发表时间：
2012-02-01
影响因子：
3.6
通讯作者：
Diaz-Araya, Guillermo
中科院分区：
文献类型：
--
作者：
Ayala, Pedro;Montenegro, Jose;Diaz-Araya, Guillermo
越来越多的证据表明内质网应激与多种疾病有关。在人类心脏中，缺血/再灌注与ER应激相关，并且未折叠蛋白反应（UPR）的几个标志物参与心脏重塑和纤维化。在这里，我们使用异丙肾上腺素（ISO）注射作为体内心脏纤维化的模型。ISO在内皮细胞受损区域诱导显著的心肌细胞损失和胶原沉积。这些反应伴随着蛋白质水平的增加，管腔！ER伴侣RIP和PDI，以及UPR效应CHOP的增加。化学伴侣4-苯基丁酸（4-PBA）的使用防止了UPR的激活，管腔伴侣的增加，并且还导致胶原沉积减少，心肌细胞损失到受损区域。我们的研究结果表明，在体内诱导的心脏损伤和纤维化的β-肾上腺素能受体激动剂ISO是密切相关的ER应激信号通路，并与外源性4-PBA增加ER腔折叠能力是一个强大的战略，防止心脏纤维化的发展。此外，4-PBA可防止心肌细胞的丢失。我们的数据表明，ER应激途径的衰减与药理学化合物，如化学伴侣4-PBA可以防止心脏纤维化和不良重塑的发展。(C)2011 Elsevier Inc. All rights reserved.
Increasing evidence indicates that endoplasmic reticulum (ER) stress is involved in various diseases. In the human heart, ischemia/reperfusion has been correlated to ER stress, and several markers of the unfolded protein response (UPR) participate during cardiac remodeling and fibrosis. Here, we used isoproterenol (ISO) injection as a model for in vivo cardiac fibrosis. ISO induced significant cardiomyocyte loss and collagen deposition in the damaged areas of the endocardium. These responses were accompanied by an increase in the protein levels of the lumina! ER chaperones RIP and PDI, as well as an increase in the UPR effector CHOP. The use of the chemical chaperone 4-phenylbutyric acid (4-PBA) prevented the activation of the UPR, the increase in luminal chaperones and also, leads to decreased collagen deposition, cardiomyocyte loss into the damaged zones. Our results suggest that cardiac damage and fibrosis induced in vivo by the beta-adrenergic agonist ISO are tightly related to ER stress signaling pathways, and that increasing the ER luminal folding capacity with exogenously administrated 4-PBA is a powerful strategy for preventing the development of cardiac fibrosis. Additionally, 4-PBA might prevent the loss of cardiomyocytes. Our data suggests that the attenuation of ER stress pathways with pharmacological compounds such as the chemical chaperone 4-PBA can prevent the development of cardiac fibrosis and adverse remodeling. (C) 2011 Elsevier Inc. All rights reserved.