Jensen Brian C, Bultman Scott J, Holley Darcy, Tang Wei, de Ridder Gustaaf, Pizzo Salvatore, Bowles Dawn, Willis Monte S
Division of Cardiology, Department of Internal Medicine, University of North Carolina, Chapel Hill, NC 27599, USA.
McAllister Heart Institute, University of North Carolina, Chapel Hill, NC 27599, USA.
Int J Clin Exp Med. 2017;10(1):1051-1058. Epub 2017 Jan 30.
The cellular environment of the mammalian heart constantly is challenged with environmental and intrinsic pathological insults, which affect the proper folding of proteins in heart failure. The effects of damaged or misfolded proteins on the cell can be profound and result in a process termed "proteotoxicity". While proteotoxicity is best known for its role in mediating the pathogenesis of neurodegenerative diseases such as Alzheimer's disease, its role in human heart failure also has been recognized. The UPR involves three branches, including PERK, ATF6, and IRE1. In the presence of a misfolded protein, the GRP78 molecular chaperone that normally interacts with the receptors PERK, ATF6, and IRE-1 in the endoplasmic reticulum detaches to attempt to stabilize the protein. Mouse models of cardiac hypertrophy, ischemia, and heart failure demonstrate increases in activity of all three branches after removing GRP78 from these internal receptors. Recent studies have linked elevated PERK and CHOP in vitro with regulation of ion channels linked with human systolic heart failure. With this in mind, we specifically investigated ventricular myocardium from 10 patients with a history of conduction system defects or arrhythmias for expression of UPR and autophagy genes compared to myocardium from non-failing controls. We identified elevated , and mRNA, along with XBP-1-regulated mRNA, indicative of activation of the UPR in human heart failure with arrhythmias.
哺乳动物心脏的细胞环境不断受到环境和内在病理损伤的挑战，这些损伤会影响心力衰竭时蛋白质的正确折叠。受损或错误折叠的蛋白质对细胞的影响可能是深远的，并导致一个称为“蛋白毒性”的过程。虽然蛋白毒性在介导神经退行性疾病（如阿尔茨海默病）的发病机制中最为人所知，但其在人类心力衰竭中的作用也已得到认可。未折叠蛋白反应（UPR）涉及三个分支，包括蛋白激酶R样内质网激酶（PERK）、活化转录因子6（ATF6）和肌醇需求酶1（IRE1）。在存在错误折叠蛋白的情况下，通常在内质网中与受体PERK、ATF6和IRE-1相互作用的葡萄糖调节蛋白78（GRP78）分子伴侣会分离，试图稳定蛋白质。心脏肥大、缺血和心力衰竭的小鼠模型表明，从这些内部受体中去除GRP78后，所有三个分支的活性都会增加。最近的研究将体外PERK和C/EBP同源蛋白（CHOP）的升高与与人类收缩性心力衰竭相关的离子通道调节联系起来。考虑到这一点，我们专门研究了10名有传导系统缺陷或心律失常病史患者的心室心肌，以比较与非衰竭对照组心肌中UPR和自噬基因的表达。我们发现， 、 和 信使核糖核酸（mRNA）升高，以及XBP-1调节的 信使核糖核酸升高，表明心律失常性人类心力衰竭中UPR被激活。
