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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2005;25:2404.)
© 2005 American Heart Association, Inc.

Atherosclerosis and Lipoproteins

Trichostatin A Exacerbates Atherosclerosis in Low Density Lipoprotein Receptor–Deficient Mice

Jae-Hoon Choi; Ki-Hoan Nam; Jiyun Kim; Min Won Baek; Jeong-Euy Park; Hyun-Young Park; Ho Jeong Kwon; Oh-Seung Kwon; Dae-Yong Kim; Goo Taeg Oh

From the Departments of Veterinary Pathology (J-H.C., D.Y.K.) and Laboratory Animal Medicine (M.W.B.), College of Veterinary Medicine and School of Agricultural Biotechnology, Seoul National University, Seoul; the Laboratory of Cardiovascular Genomics (J-H.C., G.T.O.), Division of Molecular Life Science, Ewha Womans University, Seoul; the Laboratory of Animal Model Evaluation (K-H.N., J.K.), Korea Research Institute of Bioscience and Biotechnology, Dae-jeon; the Department of Internal Medicine (J.E.P.), College of Medicine, Sungkyunkwan University, Suwon; the Department of Biomedical Sciences (H.Y.P.), Division of Genetic Diseases, National Institute of Health, Seoul; the Department of Biotechnology (H.J.K.), Yonsei University, Seoul; and Bioanalysis and Biotransformation Research Center (O.-S.K), Korea Institute of Science and Technology, Seoul, Korea.

Correspondence to Dr Goo Taeg Oh, Laboratory of Cardiovascular Genomics, Division of Molecular Life Sciences, Ewha Womans University, Seoul, Republic of Korea, 120-750. E-mail gootaeg{at}ewha.ac.kr; or Dr Dae-Yong Kim, Department of Veterinary Pathology, College of Veterinary Medicine, Seoul National University, Seoul, Republic of Korea, 151-742. E-mail daeyong@snu.ac.kr

Objective— Histone acetylation has been shown to be involved in expression of a restricted set of cellular genes including various proinflammatory molecules. We aimed to investigate the relationship between histone acetylation and atherosclerosis.

Methods and Results— In low-density lipoprotein (LDL) receptor-deficient (Ldlr^–/–) mice fed an atherogenic diet for 4 or 8 weeks, trichostatin A (TSA), a specific histone deacetylase inhibitor, exacerbated atherosclerosis without alteration on plasma lipid profiles. When we assayed the effects of TSA on expressions of oxidized LDL (oxLDL) receptors on RAW264.7 macrophage, we found that TSA increased CD36 mRNA and protein, as well as cell surface expression of CD36. TSA also increased acetylation at the CD36 promoter region. The uptake of 1,1'-dioctadecyl-3,3,3',3'-tetramethylindocarbocyanine percholate (Dil)-labeled oxLDL was enhanced in RAW264.7 macrophage by TSA. Furthermore, TSA treatment increased CD36 mRNA expression in aorta, and SRA, tumor necrosis factor (TNF)-, and vascular cell adhesion molecule-1 (VCAM-1) were also elevated, whereas IL-6 and IL-1ß expressions were decreased.

Conclusions— Our findings suggest that histone acetylation could play some role in atherogenesis by modulating expressions of oxLDL receptor and some proatherogenic genes. Therefore, our results indicate that increased histone acetylation may affect the progress of atherosclerosis.

We investigated the effect of trichostatin A, a specific histone deacetylase inhibitor, on atherosclerosis of LDL receptor–deficient mice. TSA significantly increased the formation of fatty streak lesion and macrophage infiltration possibly by enhancing the expression of CD36 and other proatherogenic molecules, suggesting the role of histone acetylation in atherogenesis.

Key Words: atherosclerosis • histone acetylatione • scavenger receptors • trichostatin A

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