Protein kinase R-like endoplasmic reticulum kinase and glycogen synthase kinase-3α/β regulate foam cell formation

Abstract

This article is available online at http://www.jlr.org cause of cerebrovascular and cardiovascular diseases, which together account for a third of all deaths in Western societies ( 1, 2 ). Multiple risk factors contribute to the initiation and progression of atherosclerosis including diabetes mellitus, hypertension, obesity, dyslipidemia, a sedentary life style, and smoking ( 3 ). One of the hallmark features of every stage of atherogenesis, from the fatty streak to the complex plaque, is the presence of lipid-laden macrophages known as foam cells. Intimal macrophage/foam cells accumulate lipids from LDL and modifi ed LDL particles and secrete a variety of infl ammatory cytokines. In advanced plaques, foam cells undergo apoptosis, thereby contributing to the formation of a highly thrombotic, lipid rich, necrotic core [reviewed by Moore and Tabas ( 4 )]. The molecular events that promote the initiation and development of atherosclerosis are poorly understood. A better understanding of the signaling networks that regulate foam cell formation and atherosclerotic plaque development may lead to the identifi cation of novel therapeutic targets.The endoplasmic reticulum (ER) is the organelle responsible for the proper folding, modifi cation, and processing of secretory, transmembrane, and ER resident proteins. If the processing capacity of the ER is overwhelmed, unfolded or misfolded proteins begin to accumulate, a condition known as ER stress. The accumulation of misfolded proteins triggers the initiation of the unfolded protein response (UPR), which is composed of three signaling cascades regulated by ER transmembrane Atherosclerosis is an infl ammatory disease within the walls of medium and large arteries ( 1 ). It is the leading C. S.

Deletion of Myeloid GSK3α Attenuates Atherosclerosis and Promotes an M2 Macrophage Phenotype

“…12,19,25,26 We have extended these findings and present the first evidence suggesting that GSK3α regulates macrophage, but not monocyte, polarization. Although deletion of GSK3α does not affect Ly6C hi/int/lo monocyte populations, it does shift macrophage polarization toward an M2 phenotype and away from an M1 phenotype.…”

“…Our previous results have suggested that endoplasmic reticulum stress activates GSK3α/β via induction of the PERK pathway. 12,20 Recently, the serine/threonine kinase AKT has been shown to modulate atherosclerosis and macrophage polarization. 47 This is intriguing because AKT is activated by endoplasmic reticulum stress and is a known regulator of GSK3α/β.…”

“…12,19,20,24 However, the homolog-specific functions of GSK3α and GSK3β in hepatic lipid metabolism have not been determined. Therefore, we analyzed lipid metabolism in the liver of HFD-fed LLαKO and LLβKO mice.…”

“…11 Originally described as a regulator of glycogen synthase and β-catenin, GSK3α/β is now recognized to be a target of several signaling networks, including insulin/PI3K (phosphoinositide 3-kinase)/ AKT (protein kinase B), MAPKs (mitogen-activated protein kinase), and endoplasmic reticulum stress. 11,12 Although GSK3α and GSK3β share several common substrates, they are not redundant and seem to have distinct functions. [13][14][15] Wholebody GSK3α-deficient mice are viable and develop normally, whereas GSK3β deletion is embryonically lethal.…”

Proteomic analyses of brain tumor cell lines amidst the unfolded protein response

“…GSK3B phosphorylation is functionally inhibitory and anti-apoptotic, improving survival of UPR-stressed tumor cells (uniquely stressed by activated A2M [75]). In other scenarios, however, UPR-induced cells activate (dephosphorylate) GSK3B [76, 77]. PKB/AKT is one of the major hubs in signal transduction with impacts in tumorigenesis and metabolism [78].…”