Department of Biological Sciences, Indian Institute of Science Education and Research, Mohali, S.A.S. Nagar, Punjab 140306, India.
Biochem J. 2020 Sep 18;477(17):3123-3130. doi: 10.1042/BCJ20200429.
Heart failure results from the heart's inability to carryout ventricular contraction and relaxation, and has now become a worldwide problem. During the onset of heart failure, several signatures are observed in cardiomyocytes that includes fetal reprogramming of gene expression where adult genes are repressed and fetal genes turned on, endoplasmic reticulum stress and oxidative stress. In this short review and analysis, we examine these different phenomenon from the viewpoint of the glutathione cycle and the role of the recently discovered Chac1 enzyme. Chac1, which belongs to the family of γ-glutamylcyclotransferases, is a recently discovered member of the glutathione cycle, being involved in the cytosolic degradation of glutathione. This enzyme is induced during the Endoplasmic Stress response, but also in the developing heart. Owing to its exclusive action on reduced glutathione, its induction leads to an increase in the oxidative redox potential of the cell that also serves as signaling mechanism for calcium ions channel activation. The end product of Chac1 action is 5-oxoproline, and studies with 5-oxoprolinase (OPLAH), an enzyme of the glutathione cycle has revealed that down-regulation of OPLAH can lead to the accumulation of 5-oxproline which is an important factor in heart failure. With these recent findings, we have re-examined the roles and regulation of the enzymes in the glutathione cycle which are central to these responses. We present an integrated view of the glutathione cycle in the cellular response to heart failure.
心力衰竭是由于心脏无法进行心室收缩和舒张而导致的，现在已经成为一个全球性的问题。在心力衰竭发作时，心肌细胞中观察到几种特征，包括基因表达的胎儿重编程，即成人基因被抑制，胎儿基因被激活，内质网应激和氧化应激。在这篇简短的综述和分析中，我们从谷胱甘肽循环和最近发现的 Chac1 酶的角度来研究这些不同的现象。Chac1 属于 γ-谷氨酰环转移酶家族，是谷胱甘肽循环的一个新成员，参与细胞溶质中谷胱甘肽的降解。该酶在内质网应激反应中被诱导，也在发育中的心脏中被诱导。由于其对还原型谷胱甘肽的特异性作用，其诱导导致细胞氧化还原电势增加，这也是钙离子通道激活的信号机制。Chac1 作用的终产物是 5-氧脯氨酸，对谷胱甘肽循环中的 5-氧脯氨酸酶（OPLAH）的研究表明，OPLAH 的下调可导致 5-氧脯氨酸的积累，而 5-氧脯氨酸是心力衰竭的一个重要因素。有了这些新发现，我们重新审视了谷胱甘肽循环中对这些反应起核心作用的酶的作用和调节。我们提出了一个细胞对心力衰竭反应中谷胱甘肽循环的综合观点。
