Department of Cardiovascular Medicine, Osaka University Graduate School of Medicine, 2-2 Yamadaoka, Suita 565-0871, Osaka, Japan.
J Mol Cell Cardiol. 2010 Jun;48(6):1105-10. doi: 10.1016/j.yjmcc.2009.10.026. Epub 2009 Nov 12.
The endoplasmic reticulum (ER) is an organelle involved in protein folding, calcium homeostasis, and lipid biosynthesis. Various factors that interfere with ER function lead to accumulation of unfolded proteins, including oxidative stress, ischemia, disturbance of calcium homeostasis, and overexpression of normal and/or incorrectly folded proteins. The resulting ER stress triggers the unfolded protein response (UPR) that induces signal transduction events to reduce the accumulation of unfolded proteins by increasing ER resident chaperones, inhibiting protein translation, and accelerating the degradation of unfolded proteins. However, if stress is severe and/or prolonged, the ER also initiates apoptotic signaling that includes induction of the pro-apoptotic transcriptional factor C/EBP homologous protein, activation of c-Jun amino-terminal kinase, and cleavage of caspase-12. These ER-initiated events lead to cell death via mitochondria-dependent and -independent apoptotic pathways. Furthermore, the B cell lymphoma 2 family of proteins expressed on the ER and mitochondria are also involved in regulating cell death due to ER stress. Thus, the ER is now recognized as a vitally important organelle that can decide cell survival or death. Recent animal and human studies have revealed that the UPR and ER-initiated apoptosis are implicated in the pathophysiology of various cardiovascular diseases, including heart failure, ischemic heart disease, the development of atherosclerosis, and plaque rupture. Improved understanding of the molecular mechanisms underlying UPR activation and ER-initiated apoptosis in cardiovascular disease will provide us with new targets for drug discovery and therapeutic intervention.
内质网（ER）是参与蛋白质折叠、钙稳态和脂质生物合成的细胞器。干扰 ER 功能的各种因素导致未折叠蛋白质的积累，包括氧化应激、缺血、钙稳态紊乱和正常和/或错误折叠蛋白质的过表达。由此产生的 ER 应激触发未折叠蛋白反应（UPR），通过增加 ER 驻留伴侣、抑制蛋白质翻译和加速未折叠蛋白质的降解，诱导信号转导事件来减少未折叠蛋白质的积累。然而，如果应激严重和/或持久，ER 还会启动凋亡信号，包括诱导促凋亡转录因子 C/EBP 同源蛋白、激活 c-Jun 氨基末端激酶和切割半胱天冬酶-12。这些 ER 启动的事件通过线粒体依赖性和非依赖性凋亡途径导致细胞死亡。此外，在 ER 和线粒体上表达的 B 细胞淋巴瘤 2 蛋白家族也参与调节由于 ER 应激引起的细胞死亡。因此，ER 现在被认为是一个至关重要的细胞器，可以决定细胞的存活或死亡。最近的动物和人类研究表明，UPR 和 ER 启动的凋亡参与了各种心血管疾病的病理生理学，包括心力衰竭、缺血性心脏病、动脉粥样硬化的发展和斑块破裂。对 UPR 激活和 ER 启动的凋亡在心血管疾病中的分子机制的深入了解将为我们提供药物发现和治疗干预的新靶点。
