title: Histone deacetylase 9 represses cholesterol efflux and alternatively activated macrophages in atherosclerosis development.
abstract: OBJECTIVE
  Recent genome-wide association studies revealed that a genetic variant in the loci corresponding to histone deacetylase 9 (HDAC9) is associated with large vessel stroke. HDAC9 expression was upregulated in human atherosclerotic plaques in different arteries. The molecular mechanisms how HDAC9 might increase atherosclerosis is not clear.
  
  
  RESULTS
  In this study, we show that systemic and bone marrow cell deletion of HDAC9 decreased atherosclerosis in LDLr(-/-) (low density lipoprotein receptor) mice with minimal effect on plasma lipid concentrations. HDAC9 deletion resulted upregulation of lipid homeostatic genes, downregulation of inflammatory genes, and polarization toward an M2 phenotype via increased accumulation of total acetylated H3 and H3K9 at the promoters of ABCA1 (ATP-binding cassette transporter), ABCG1, and PPAR-γ (peroxisome proliferator-activated receptor) in macrophages.
  
  
  CONCLUSIONS
  We conclude that macrophage HDAC9 upregulation is atherogenic via suppression of cholesterol efflux and generation of alternatively activated macrophages in atherosclerosis.
authors.affiliation: From the Departments of Internal Medicine/Rheumatology and Immunology (Q.C., N.M.), Pathology/Lipid Sciences (S.R., R.S.C., J.S.P.), and Biochemistry (J.S.P.), Wake Forest School of Medicine, Winston-Salem, NC; and Departments of Internal Medicine and Physiology, The University of Texas Southwestern Medical Center, Dallas (J.J.R.).
authors.forename: Qiang
authors.initials: Q
authors.lastname: Cao
authors.affiliation: From the Departments of Internal Medicine/Rheumatology and Immunology (Q.C., N.M.), Pathology/Lipid Sciences (S.R., R.S.C., J.S.P.), and Biochemistry (J.S.P.), Wake Forest School of Medicine, Winston-Salem, NC; and Departments of Internal Medicine and Physiology, The University of Texas Southwestern Medical Center, Dallas (J.J.R.).
authors.forename: Shunxing
authors.initials: S
authors.lastname: Rong
authors.affiliation: From the Departments of Internal Medicine/Rheumatology and Immunology (Q.C., N.M.), Pathology/Lipid Sciences (S.R., R.S.C., J.S.P.), and Biochemistry (J.S.P.), Wake Forest School of Medicine, Winston-Salem, NC; and Departments of Internal Medicine and Physiology, The University of Texas Southwestern Medical Center, Dallas (J.J.R.).
authors.forename: Joyce J
authors.initials: JJ
authors.lastname: Repa
authors.affiliation: From the Departments of Internal Medicine/Rheumatology and Immunology (Q.C., N.M.), Pathology/Lipid Sciences (S.R., R.S.C., J.S.P.), and Biochemistry (J.S.P.), Wake Forest School of Medicine, Winston-Salem, NC; and Departments of Internal Medicine and Physiology, The University of Texas Southwestern Medical Center, Dallas (J.J.R.).
authors.forename: Richard
authors.initials: R
authors.lastname: St Clair
authors.affiliation: From the Departments of Internal Medicine/Rheumatology and Immunology (Q.C., N.M.), Pathology/Lipid Sciences (S.R., R.S.C., J.S.P.), and Biochemistry (J.S.P.), Wake Forest School of Medicine, Winston-Salem, NC; and Departments of Internal Medicine and Physiology, The University of Texas Southwestern Medical Center, Dallas (J.J.R.).
authors.forename: John S
authors.initials: JS
authors.lastname: Parks
authors.affiliation: From the Departments of Internal Medicine/Rheumatology and Immunology (Q.C., N.M.), Pathology/Lipid Sciences (S.R., R.S.C., J.S.P.), and Biochemistry (J.S.P.), Wake Forest School of Medicine, Winston-Salem, NC; and Departments of Internal Medicine and Physiology, The University of Texas Southwestern Medical Center, Dallas (J.J.R.). nmishra@wakehealth.edu.
authors.forename: Nilamadhab
authors.initials: N
authors.lastname: Mishra
mesh_terms: D000818:Animals; D050197:Atherosclerosis / Q000097:blood / Q000201:enzymology* / Q000235:genetics / Q000517:prevention & control / Q000601:surgery; D016026:Bone Marrow Transplantation; D002454:Cell Differentiation; D002460:Cell Line; D002784:Cholesterol / Q000097:blood / Q000378:metabolism*; D002791:Cholesterol, Dietary; D004036:Diet, Atherogenic; D004041:Dietary Fats; D004790:Enzyme Induction; D005260:Female; D006655:Histone Deacetylases / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D006801:Humans; D007249:Inflammation / Q000235:genetics; D008262:Macrophage Activation; D017737:Macrophages, Peritoneal / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D047495:PPAR gamma / Q000096:biosynthesis / Q000235:genetics; D010743:Phospholipids / Q000097:blood; D011973:Receptors, LDL / Q000172:deficiency / Q000235:genetics; D012097:Repressor Proteins / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D014280:Triglycerides / Q000097:blood
chemical_list: D002791:Cholesterol, Dietary; D004041:Dietary Fats; D047495:PPAR gamma; D010743:Phospholipids; D011973:Receptors, LDL; D012097:Repressor Proteins; D014280:Triglycerides; D002784:Cholesterol; C486545:Hdac9 protein, mouse; D006655:Histone Deacetylases
keywords: atherosclerosis; epigenomics; histones; istone deacetylases; macrophages