Qiang Cao1, Shunxing Rong1, Joyce J Repa1, Richard St Clair1, John S Parks1, Nilamadhab Mishra2. 1. 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.). 2. 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.
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. APPROACH AND 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.
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 humanatherosclerotic plaques in different arteries. The molecular mechanisms how HDAC9 might increase atherosclerosis is not clear. APPROACH AND RESULTS: In this study, we show that systemic and bone marrow cell deletion of HDAC9decreased 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.
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