Inhibition of Endoplasmic Reticulum Stress and Atherosclerosis by 2-Aminopurine in Apolipoprotein E-Deficient Mice

We previously reported that the apolipoprotein (apo) B48-carrying lipoproteins obtained from apoE knockout (apoE (−/−)) mice, so called E(−)/B48 lipoproteins, transformed mouse macrophages into foam cells and enhanced the phosphorylation of eukaryotic translation initiation factor 2α (eIF-2α). Furthermore, the eIF-2α 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 apoE (−/−) mice. Our results showed that the level of food intake, bodyweight, plasma cholesterol, and triglycerides was comparable in apoE (−/−) 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 apoE (−/−) mice were reduced by about 55% and 39%, respectively, compared to samples from untreated control apoE (−/−) mice. In addition, the 2-AP-treated apoE (−/−) mice showed a significant decrease in glucose-regulated protein 78 (GRP78) and phosphorylated eIF-2α in their aortic samples as compared to levels in untreated control apoE (−/−) mice. These observations suggest that endoplasmic reticulum stress is a causal mechanism for the development of atherosclerosis in apoE (−/−) mice and that therapeutic strategies can be developed for using eIF-2α phosphorylation inhibitors, such as 2-AP, to prevent or treat atherosclerosis.