trichostatin-a and Atherosclerosis

Topics: Animals; Apolipoproteins E; Atherosclerosis; ATP Binding Cassette Transporter 1; ATP Binding Cassette Transporter, Subfamily G, Member 1; CCAAT-Enhancer-Binding Protein-alpha; Diet, High-Fat; Epigenesis, Genetic; Foam Cells; Histone Deacetylase Inhibitors; Hydroxamic Acids; Macrophages, Peritoneal; Mice; Mice, Knockout; PPAR gamma; RAW 264.7 Cells

Trichostatin A (TSA) and suberoylanilide hydroxamic acid (SAHA) were reported in our recent publication as novel human high density lipoprotein (HDL) receptor CD36 and Lysosomal integral membrane protein-II Analogous-1 (CLA-1) up-regulators. As part of a broader effort to more fully explore the structure-activity relationships (SAR) of CLA-1 up-regulators, we synthesized a series of hydroxamic acid derivatives and evaluated their CLA-1 up-regulating activities in HepG2 cells. Some compounds exhibited over 10-fold up-regulation of CLA-1 expression in HepG2 cells at 10 μg/mL concentration. The compound 1g showed the best potency, with a lower EC(50) than TSA (EC(50) = 0.32 μM versus 1.2 μM). These compounds provide early new CLA-1 up-regulators with potential for treating atherosclerosis.

Topics: Animals; Atherosclerosis; Dose-Response Relationship, Drug; Hep G2 Cells; Histone Deacetylase Inhibitors; Humans; Hydroxamic Acids; Lipoproteins, HDL; Mice; Molecular Structure; Scavenger Receptors, Class B; Structure-Activity Relationship; Up-Regulation; Vorinostat

Macrophage-triggered chronic inflammation and smooth muscle cell-initiated vascular remodeling are two major pathophysiologic events during atherogenesis. Major histocompatibility class II (MHC II) transactivator (CIITA) is a key mediator of these processes through transcriptional regulation of interferon gamma (IFN-gamma) induced MHC II activation and type I collagen repression. Transcriptional activity of CIITA is regulated by multiple post-translational modifications. Here we report that CIITA and histone deacetylase 2 (HDAC2) interact in smooth muscle cells and macrophages as assayed by co-immunoprecipitations. HDAC2 deacetylates CIITA whereas both the HDAC inhibitor trichostatin A (TSA) and over-expression of HDAC2 interfering RNA increase CIITA acetylation. HDAC2 down-regulates CIITA recruitment to target promoters as evidenced by chromatin immunoprecipitation assays, and suppresses MHC II activation and collagen repression mediated by CIITA in luciferase reporter assays. Quantitative PCR reveals that TSA enhances MHC II activation and collagen repression by IFN-gamma. Wild type but not enzyme-deficient HDAC2 promotes the degradation of CIITA protein, whereas TSA and the proteasome inhibitor MG132 restore CIITA activity by stabilizing CIITA protein and increasing its association with target promoters. Furthermore, TSA treatment enhances the association of CIITA with the transcription factor RFX5, which ameliorates the down-regulation of CIITA recruitment to target promoters by HDAC2. In conclusion, our data suggest that HDAC2 antagonizes CIITA activity by committing CIITA to protein degradation and decreasing the interaction of CIITA with RFX5 in a deacetylation-dependent manner. Therefore, modulating CIITA activity by targeting HDAC2 may provide potential anti-atherogenic strategies.

Topics: Acetylation; Animals; Atherosclerosis; Cell Line; Collagen Type I; Cysteine Proteinase Inhibitors; DNA-Binding Proteins; Histocompatibility Antigens Class II; Histone Deacetylase 2; Histone Deacetylase Inhibitors; Histone Deacetylases; Humans; Hydroxamic Acids; Inflammation; Interferon-gamma; Leupeptins; Macrophages; Mice; Myocytes, Smooth Muscle; Nuclear Proteins; Promoter Regions, Genetic; Protein Processing, Post-Translational; Regulatory Factor X Transcription Factors; Repressor Proteins; Trans-Activators; Transcription Factors; Transcription, Genetic

Topics: Acetylation; Animals; Atherosclerosis; Cell Line; Collagen Type I; Cysteine Proteinase Inhibitors; DNA-Binding Proteins; Histocompatibility Antigens Class II; Histone Deacetylase 2; Histone Deacetylase Inhibitors; Histone Deacetylases; Humans; Hydroxamic Acids; Inflammation; Interferon-gamma; Leupeptins; Macrophages; Mice; Myocytes, Smooth Muscle; Nuclear Proteins; Promoter Regions, Genetic; Protein Processing, Post-Translational; Regulatory Factor X Transcription Factors; Repressor Proteins; Trans-Activators; Transcription Factors; Transcription, Genetic

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.. 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.. 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.

Topics: Acetylation; Animals; Aorta; Atherosclerosis; CD36 Antigens; Cell Line; Enzyme Inhibitors; Histone Deacetylase Inhibitors; Histone Deacetylases; Histones; Hydroxamic Acids; Lipoproteins, LDL; Macrophages; Male; Mice; Mice, Inbred C57BL; Mice, Mutant Strains; Monocytes; Promoter Regions, Genetic; Receptors, LDL