Abstract 16439: Examining the Role of Endoplasmic Reticulum Stress Induced Glycogen Synthase Kinasea-3α/β in Accelerated Atherosclerosis
Introduction Cardiovascular disease accounts for a third of all deaths in the western world, however our understanding of the molecular mechanisms of atherosclerosis development is incomplete. Our previous findings have suggested that Endoplasmic Reticulum (ER) stress plays a causative role in atherogenesis. The objective of this study is to investigate how ER stress promotes atherosclerosis with a specific focus on ER stress-induced Glycogen Synthase Kinase (GSK)-3. Methods and Results Established models of hyperglycemia (low-dose injections of streptozotocin), hyperhomocysteinemia (methionine-supplemented drinking water), and relative dyslipidemia (high fat diet) in female ApoE-/- mice were examined. A subset of mice from each group was supplemented with valproate (625 mg/kg), a compound with GSK3α/β inhibitory properties. Hyperglycemia, hyperhomocysteinemia and high fat diet elevated ER stress levels in multiple tissues, enhanced GSK3β activity, increased atherosclerotic plaque size, and induced hepatic steatosis. Valproate supplementation significantly attenuated GSK3β activation, aortic plaque development and hepatic steatosis without altering ER stress levels. Modulation of GSK3β activity by ER stress and valproate appears to involve alterations in phosphorylation. To further examine the mechanism linking ER stress to activation of pro-atherogenic pathways, wildtype Mouse Embryonic Fibroblasts (MEF) and MEFs deficient in GSK3α or GSK3β, or the ER stress response proteins PERK or IRE1α were treated with the ER stress inducing agents glucosamine (GLN) or tunicamycin (TM). In wildtype MEFs GLN and TM induced the expression of genes involved in lipid biosynthesis and promoted lipid accumulation. ER stress-induced lipid accumulation was attenuated in PERK-/-, GSK3α-/- and GSK3β-/- MEFs. Inhibition of GSK3α/β attenuated lipid accumulation in wild type and IRE1α-/- MEFs, however did not affect lipid levels in PERK-/- MEFs. Lipid accumulation could be restored in PERK-/- MEFs by overexpressing a constitutively active form of GSK3β. Conclusions These findings support the existence of a common mechanism by which conditions of ER stress promote signaling through PERK and GSK3α/β to induce pro-atherogenic pathways.
- © 2012 by American Heart Association, Inc.