CREG1 ameliorates myocardial fibrosis associated with autophagy activation and Rab7 expression
CREG1 ameliorates myocardial fibrosis associated with autophagy activation and Rab7 expression
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CREG1 可改善与自噬激活和 Rab7 表达相关的心肌纤维化。
DOI：
10.1016/j.bbadis.2014.05.027
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发表时间：
2015-02-01
影响因子：
6.2
通讯作者：
Han, Ya-ling
中科院分区：
文献类型：
--
作者：
Yan, Cheng-hui;Li, Yang;Han, Ya-ling
在遭受应激的心肌细胞中，自噬激活是一种关键的生存机制，可以保持细胞能量状态，同时降解受损的蛋白质和细胞器。然而，人们对控制这种自噬反应的机制知之甚少。 El A基因的细胞阻遏蛋白(CREG1)是一种进化上保守的溶酶体蛋白，是调节组织稳态的重要新因子，已被证明可以拮抗组织或细胞的损伤。在本研究中，我们旨在探讨CREG1在心脏自噬中的调节作用，并阐明自噬激活机制。首先，我们建立了 CREG1 单倍体不足 (Cregl(+/-)) 小鼠模型，并发现 CREG1 缺陷会加剧衰老或血管紧张素 II (Ang II) 引起的心肌纤维化。相反，外源输注重组CREG1蛋白完全逆转了心脏损伤。 Creg1(+/-) 小鼠心脏中的 CREG1 缺陷表现出获得 LC3II 和 bedin-1 的自噬体显着积聚，并且 p62 水平上调表明自噬通量清除率降低。相反，CREG1 的恢复会激活心脏自噬。此外，使用溶酶体酸化抑制剂氯喹证实 CREG1 通过激活自噬保护心脏组织免受 Ang II 诱导的纤维化。通过腺病毒感染原代心肌细胞，CREG1 的过表达与白藜芦醇同时治疗显着增加了自噬，而沉默 CREG1 则阻断了白藜芦醇诱导的自噬。这些结果表明，面对应激引起的心肌损伤，需要 CREG1 诱导的自噬来维持心脏功能。体外和体内研究均发现CREG1缺陷影响溶酶体的成熟并降低Rab7的表达，这可能参与CREG1诱导的心肌细胞自噬。这些发现表明，通过 CREG1 激活自噬可能是改善病理条件下心脏性能的可行治疗策略。本文是题为“心脏代谢疾病中的自噬和蛋白质质量控制”的特刊的一部分。 (C) 2014 Elsevier B.V. 保留所有权利。
In cardiomyocytes subjected to stress, autophagy activation is a critical survival mechanism that preserves cellular energy status while degrading damaged proteins and organelles. However, little is known about the mechanisms that govern this autophagic response. Cellular repressor of El A genes (CREG1) is an evolutionarily conserved lysosomal protein, and an important new factor in regulating tissue homeostasis that has been shown to antagonize injury of tissues or cells. In the present study, we aimed to investigate the regulatory role of CREG1 in cardiac autophagy, and to clarify autophagy activation mechanisms. First, we generated a CREG1 haploinsufficiency (Cregl(+/-)) mouse model, and identified that CREG1 deficiency aggravates myocardial fibrosis in response to aging or angiotensin II (Ang II). Conversely, exogenous infusion of recombinant CREG1 protein completely reversed cardiac damage. CREG1 deficiency in Creg1(+/-) mouse heart showed a marked accumulation of autophagosome that acquired LC3II and bedin-1, and a decrease in autophagic flux clearance as indicated by upregulating the level of p62. Inversely, restoration of CREG1 activates cardiac autophagy. Furthermore, chloroquine, an inhibitor of lysosomal acidification, was used to confirm that CREG1 protected the heart tissue against Ang II-induced fibrosis by activating autophagy. Using adenoviral infection of primary cardiomyocytes, overexpression of CREG1 with concurrent resveratrol treatment significantly increased autophagy, while silencing CREG1 blocked the resveratrol-induced autophagy. These results suggest that CREG1-induced autophagy is required to maintain heart function in the face of stress-induced myocardiac damage. Both in vitro and in vivo studies identified that CREG1 deficiency influenced the maturation of lysosomes and reduced the expression of Rab7, which might be involved in CREG1-induced cardiomyocyte autophagy. These findings suggest that autophagy activation via CREG1 may be a viable therapeutic strategy for improving cardiac performance under pathologic conditions. This article is part of a Special Issue entitled: Autophagy and protein quality control in cardiometabolic diseases. (C) 2014 Elsevier B.V. All rights reserved.