The Epidermal Growth Factor Receptor: A Missing Link Between Endoplasmic Reticulum Stress and Diabetic Complications?

See related article, pp 71–80 The endoplasmic reticulum (ER) is recognized as an organelle in which protein folding, calcium homeostasis, and lipid biosynthesis occur. The ER responds to stresses such as oxidative stress, ischemic insult, and disturbances in calcium homeostasis by upregulating ER chaperones, inhibiting protein translation, and accelerating degradation of unfolded proteins via signaling pathways collectively termed the “unfolded protein responses” (UPRs). Thus, UPRs are considered a form of cellular protection. On ER stress, the ER chaperone immunoglobulin heavy chain–binding protein (also known as HSPA5 or GRP78) binds to unfolded or misfolded proteins and dissociates from 3 well-characterized ER stress sensors, inositol-requiring 1α, double-stranded RNA-dependent protein kinase–like ER kinase, and activating transcription factor 6 to initiate the UPR pathways. However, prolonged and excessive ER stress leads to inflammation and cell apoptosis via the UPR pathways.1 In addition to the protective roles of the UPR, the literature increasingly suggests that prolonged ER stress and subsequent UPR activation likely contribute to the development and progression of various disease processes, including cardiovascular diseases such as heart failure, ischemic heart diseases, and atherosclerosis.2 Moreover, recent studies reveal that prolonged ER stress associated with metabolic syndrome leads to persistent UPRs and reduced insulin secretion, invokes oxidative stress and insulin resistance, and activates an apoptotic pathway.3 Therefore, there is strong scientific, as well as clinical, interest regarding the regulatory mechanisms and therapeutic applications of the UPR pathways associated with cardiovascular diseases. The “trans”-activation of epidermal growth factor receptor (EGFR) …