Endoplasmic reticulum stress and protein quality control in diabetic cardiomyopathy

Abstract

Endoplasmic reticulum (ER) stress, together with the unfolded protein response (UPR), is initially considered an adaptive response aiming at maintenance of ER homeostasis. Nonetheless, ER stress, when in excess, can eventually trigger cell apoptosis and loss of function. UPR is mediated by three major transmembrane proteins, including inositol-requiring enzyme 1 (IRE1), protein kinase RNA-like ER kinase (PERK), and activating transcription factor (ATF) 6. A unique role has been speculated for ER stress in the pathogenesis of diabetes mellitus (DM) and its complications. Recent studies have shown that ER stress is an early event associated with diabetic cardiomyopathy, and may be triggered by hyperglycemia, free fatty acids (FFAs) and inflammation. In this mini-review, we attempted to discuss the activation machinery for ER stress in response to these triggers en route to disrupted ER function and cellular autophagy or apoptosis, ultimately insulin resistance and development of diabetic cardiomyopathy. This article is part of a Special Issue entitled: Autophagy and protein quality control in cardiometabolic diseases.

A novel endoplasmic reticulum stress-induced apoptosis model using tunicamycin in primary cultured neonatal rat cardiomyocytes

“…Accumulating evidence demonstrates that ER stress-induced apoptosis is the key contributor to cell loss in the pathogenesis of a series of cardiovascular diseases (8,25,26). However, the detailed mechanism of ER stress in cardiovascular diseases remains unclear.…”

“…Stresses that lead to the impairment of ER function are collectively known as ER stress (6,7). ER stress triggers an evolutionarily conserved response termed the unfolded protein response (UPR), an adaptive mechanism that initially promotes organelle recovery (8). In response to ER stress, there is significant upregulation of various ER resident chaperones, such as glucose-regulated protein 94-kDa (GRP94) and glucose-regulated protein 78-kDa (GRP78) that inhibit protein synthesis and activate protein degradation (9)(10).…”

Hyperglycemia-Induced Changes in ZIP7 and ZnT7 Expression Cause Zn2+ Release From the Sarco(endo)plasmic Reticulum and Mediate ER Stress in the Heart

“…ER-stress is one of the underlying mechanisms of cardiac dysfunction including diabeticcardiomyopathy (27)(28)(29). Studies suggest that there is relationship between S(E)R function and cytosolic Zn 2+ level in diabetic rat cardiomyocytes (29; 30).…”

Time-dependent cellular response in the liver and heart in a dietary-induced obese mouse model: the potential role of ER stress and autophagy

“…Accumulating evidence indicates that protein quality control systems play an important role during the development of obesity-related metabolic diseases [2][3][4]. Cellular protein quality is mainly controlled by the endoplasmic reticulum (ER) and the autophagy system.…”

“…Shortterm administration of palmitate activates the UPR and autophagic flux in hepatocytes, whereas long-term palmitate administration induces ER stress, blocks autophagy, and causes cell death [8]. Moreover, ER stress activates autophagy via both the IRE1α-and PERK-dependent pathways in the diabetic heart; however, only the IRE1α pathway is involved in the induction of autophagy by the UPR [4]. Because there is very little evidence for the connection between cellular protein quality and the development of tissue-specific pathogenesis in obesity-related diseases, the objective of this study was to examine the effects of an HFD on ER stress, autophagy, and apoptosis in the hypertrophic liver and heart in order to evaluate the time dependency of changes in a diet-induced obesity animal model.…”