%0 Journal Article
%T Inhibition of Endoplasmic Reticulum Stress and Atherosclerosis by 2-Aminopurine in Apolipoprotein E-Deficient Mice
%A Lichun Zhou
%A Dezhi Yang
%A Dong Fang Wu
%A Zhong Mao Guo
%A Emmanuel Okoro
%A Hong Yang
%J ISRN Pharmacology
%D 2013
%R 10.1155/2013/847310
%X We previously reported that the apolipoprotein (apo) B48-carrying lipoproteins obtained from apoE knockout ( ) mice, so called E£¿/B48 lipoproteins, transformed mouse macrophages into foam cells and enhanced the phosphorylation of eukaryotic translation initiation factor 2¦Á (eIF-2¦Á). Furthermore, the eIF-2¦Á phosphorylation inhibitor, 2-aminopurine (2-AP), attenuated E£¿/B48 lipoprotein-induced foam cell formation. The present report studied the effect of 2-AP on atherosclerosis in mice. Our results showed that the level of food intake, bodyweight, plasma cholesterol, and triglycerides was comparable in mice treated with or without 2-AP. However, the mean size of atherosclerotic lesions in the aorta sinus as well as the surface area of the entire aorta of 2-AP-treated mice were reduced by about 55% and 39%, respectively, compared to samples from untreated control mice. In addition, the 2-AP-treated mice showed a significant decrease in glucose-regulated protein 78 (GRP78) and phosphorylated eIF-2¦Á in their aortic samples as compared to levels in untreated control mice. These observations suggest that endoplasmic reticulum stress is a causal mechanism for the development of atherosclerosis in mice and that therapeutic strategies can be developed for using eIF-2¦Á phosphorylation inhibitors, such as 2-AP, to prevent or treat atherosclerosis. 1. Introduction The endoplasmic reticulum (ER) fulfills multiple cellular functions. Once ER functions are perturbed by various pathological conditions, unfolded or misfolded proteins accumulate in the ER lumen, resulting in ER stress characterized by increasing ER molecular chaperones and diminishing global protein synthesis [1]. Activation of the signaling network in response to ER stress is known as unfolded protein response (UPR). There are three distinct UPR signaling pathways triggered in response to ER stress, which are mediated by (1) RNA-dependent protein kinase-like endoplasmic reticulum kinase (PERK), (2) activating transcription factor 6 (ATF6), and (3) inositol-requiring enzyme 1 (IRE1), respectively, [2, 3]. Under physiological conditions, PERK, ATF6, and IRE1 are associated with the abundant luminal chaperone Bip (also known as glucose-regulated protein 78, GRP78). This interaction keeps PERK, ATF6, and IRE1 in an inactive state. When the ER is overloaded with newly synthesized proteins or is stimulated by agents that cause unfolded proteins to accumulate, GRP78/Bip preferentially associates with the unfolded proteins, releasing PERK, ATF6, and IRE1 to activate downstream signaling molecules. In the
%U http://www.hindawi.com/journals/isrn.pharmacology/2013/847310/