Trichostatin A exacerbates atherosclerosis in low density lipoprotein receptor-deficient mice.
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.


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)-alpha, and vascular cell adhesion molecule-1 (VCAM-1) were also elevated, whereas IL-6 and IL-1beta 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.
Choi
Jae-Hoon
JH
Department of Veterinary Pathology, College of Veterinary Medicine, School of Agricultural Biotechnology, Seoul National University, Seoul, Korea.
Nam
Ki-Hoan
KH
Kim
Jiyun
J
Baek
Min Won
MW
Park
Jeong-Euy
JE
Park
Hyun-Young
HY
Kwon
Ho Jeong
HJ
Kwon
Oh-Seung
OS
Kim
Dae-Yong
DY
Oh
Goo Taeg
GT
D000107:Acetylation / Q000187:drug effects; D000818:Animals; D001011:Aorta / Q000378:metabolism / Q000473:pathology; D050197:Atherosclerosis / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D018955:CD36 Antigens / Q000235:genetics; D002460:Cell Line; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D056572:Histone Deacetylase Inhibitors; D006655:Histone Deacetylases / Q000378:metabolism; D006657:Histones / Q000378:metabolism; D006877:Hydroxamic Acids / Q000494:pharmacology*; D008077:Lipoproteins, LDL / Q000493:pharmacokinetics; D008264:Macrophages / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D009000:Monocytes / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D011401:Promoter Regions, Genetic / Q000502:physiology; D011973:Receptors, LDL / Q000235:genetics* / Q000378:metabolism
D018955:CD36 Antigens; D004791:Enzyme Inhibitors; D056572:Histone Deacetylase Inhibitors; D006657:Histones; D006877:Hydroxamic Acids; D008077:Lipoproteins, LDL; D011973:Receptors, LDL; C099252:oxidized low density lipoprotein; C012589:trichostatin A; D006655:Histone Deacetylases