title: Inhibition of endoplasmic reticulum stress and atherosclerosis by 2-aminopurine in apolipoprotein e-deficient mice.
abstract: 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 2 α (eIF-2 α ). Furthermore, the eIF-2 α 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-2 α 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-2 α phosphorylation inhibitors, such as 2-AP, to prevent or treat atherosclerosis.
authors: Department of Physiology, Meharry Medical College, Nashville, TN 37208, USA.
authors: Lichun
authors: L
authors: Zhou
authors: Dezhi
authors: D
authors: Yang
authors: Dong Fang
authors: DF
authors: Wu
authors: Zhong Mao
authors: ZM
authors: Guo
authors: Emmanuel
authors: E
authors: Okoro
authors: Hong
authors: H
authors: Yang
references: J Lipid Res. 1999 Nov;40(11):1933-49
references: 10552997
references: Proc Natl Acad Sci U S A. 1992 May 15;89(10):4471-5
references: 1584779
references: Biochem Soc Trans. 2006 Feb;34(Pt 1):7-11
references: 16246168
references: Annu Rev Physiol. 2013;75:49-67
references: 23020580
references: J Clin Invest. 2005 Oct;115(10):2656-64
references: 16200199
references: Circulation. 2004 Jul 13;110(2):207-13
references: 15210586
references: J Pharmacol Exp Ther. 2008 Aug;326(2):395-405
references: 18463320
references: PLoS One. 2012;7(12):e51011
references: 23300532
references: Mutat Res. 2005 Jan 6;569(1-2):29-63
references: 15603751
references: J Biol Chem. 2005 May 27;280(21):20331-9
references: 15788408
references: J Lipid Res. 2005 Jul;46(7):1380-7
references: 15863839
references: J Lipid Res. 1999 Aug;40(8):1529-38
references: 10428991
references: J Biol Chem. 2009 Jan 9;284(2):1106-15
references: 19017641
references: Curr Opin Cell Biol. 2006 Aug;18(4):444-52
references: 16781856
references: Nat Cell Biol. 2003 Sep;5(9):781-92
references: 12907943
references: Circulation. 2005 Apr 12;111(14):1814-21
references: 15809369
references: Mech Ageing Dev. 2002 Apr 30;123(8):1121-31
references: 12044962
references: Handb Exp Pharmacol. 2006;(172):69-91
references: 16610355
references: Atherosclerosis. 2003 Aug;169(2):215-24
references: 12921972
references: Mol Biol Cell. 2011 Nov;22(22):4390-405
references: 21917591
references: J Biochem. 2006 Jul;140(1):23-38
references: 16877765
references: J Lipid Res. 2007 Dec;48(12):2571-8
references: 17720994
references: Free Radic Biol Med. 2011 Jul 1;51(1):97-106
references: 21569840
references: J Bioanal Biomed. 2010 Oct 6;2:113-120
references: 21552349
references: Arterioscler Thromb Vasc Biol. 2004 Jan;24(1):147-54
references: 14615393