Hsiao-Huei Chen1, Kianoosh Keyhanian2, Xun Zhou2, Ragnar O Vilmundarson2, Naif A M Almontashiri2, Shelly A Cruz2, Nihar R Pandey2, Nida Lerma Yap2, Tiffany Ho2, Chloe A Stewart2, Hua Huang2, Aswin Hari2, Michele Geoffrion2, Ruth McPherson2, Katey J Rayner2, Alexandre F R Stewart1. 1. From the Department of Cellular and Molecular Medicine, University of Ottawa, and the Ottawa Hospital Research Institute, Ottawa, Ontario, Canada (H.-H.C., K.K., X.Z., S.A.C., N.R.P., C.A.S., H.H., A.H.); the Department of Biochemistry, Microbiology and Immunology, University of Ottawa, and the University of Ottawa Heart Institute, Ottawa, Ontario, Canada (R.O.V., N.A.M.A., N.L.Y., T.H., M.G., R.M., K.J.R., A.F.R.S.); and Department of Medicine, University of Ottawa, Ottawa, Ontario, Canada (H.H.C., R.M., A.F.R.S.). hchen@uottawa.ca astewart@ottawaheart.ca. 2. From the Department of Cellular and Molecular Medicine, University of Ottawa, and the Ottawa Hospital Research Institute, Ottawa, Ontario, Canada (H.-H.C., K.K., X.Z., S.A.C., N.R.P., C.A.S., H.H., A.H.); the Department of Biochemistry, Microbiology and Immunology, University of Ottawa, and the University of Ottawa Heart Institute, Ottawa, Ontario, Canada (R.O.V., N.A.M.A., N.L.Y., T.H., M.G., R.M., K.J.R., A.F.R.S.); and Department of Medicine, University of Ottawa, Ottawa, Ontario, Canada (H.H.C., R.M., A.F.R.S.).
Abstract
RATIONALE: Inflammation impairs macrophage cholesterol clearance from vascular tissues and promotes atherosclerosis. Inflammatory macrophages suppress expression of the transcription cofactor interferon regulatory factor 2-binding protein 2 (IRF2BP2), and genetic variants near IRF2BP2 associate with ischemic heart disease progression in humans. OBJECTIVES: To test whether IRF2BP2 in macrophages affects atherosclerosis in mice and humans. METHODS AND RESULTS: We generated mice that delete IRF2BP2 in macrophages. IRF2BP2-deficient macrophages worsened atherosclerosis in irradiated low-density lipoprotein receptor null-recipient mice and in apolipoprotein E null mice. IRF2BP2-deficient macrophages were inflammatory and had impaired cholesterol efflux because of their inability to activate the cholesterol transporter ABCA1 in response to cholesterol loading. Their expression of the anti-inflammatory transcription factor Krüppel-like factor 2 was markedly reduced. Promoter studies revealed that IRF2BP2 is required for MEF2-dependent activation of Krüppel-like factor 2. Importantly, restoring Krüppel-like factor 2 in IRF2BP2-deficient macrophages attenuated M1 inflammatory and rescued M2 anti-inflammatory gene activation and improved the cholesterol efflux deficit by restoring ABCA1 activation in response to cholesterol loading. In a cohort of 1066 angiographic cases and 1011 controls, homozygous carriers of a deletion polymorphism (rs3045215) in the 3' untranslated region sequence of human IRF2BP2 mRNA had a higher risk of coronary artery disease (recessive model, odds ratio [95% confidence interval]=1.560 [1.179-2.065], P=1.73E-03) and had lower IRF2BP2 (and Krüppel-like factor 2) protein levels in peripheral blood mononuclear cells. The effect of this deletion polymorphism to suppress protein expression was confirmed in luciferase reporter studies. CONCLUSION: Ablation of IRF2BP2 in macrophages worsens atherosclerosis in mice, and a deletion variant that lowers IRF2BP2 expression predisposes to coronary artery disease in humans.
RATIONALE: Inflammation impairs macrophage cholesterol clearance from vascular tissues and promotes atherosclerosis. Inflammatory macrophages suppress expression of the transcription cofactor interferon regulatory factor 2-binding protein 2 (IRF2BP2), and genetic variants near IRF2BP2 associate with ischemic heart disease progression in humans. OBJECTIVES: To test whether IRF2BP2 in macrophages affects atherosclerosis in mice and humans. METHODS AND RESULTS: We generated mice that delete IRF2BP2 in macrophages. IRF2BP2-deficient macrophages worsened atherosclerosis in irradiated low-density lipoprotein receptor null-recipient mice and in apolipoprotein E null mice. IRF2BP2-deficient macrophages were inflammatory and had impaired cholesterol efflux because of their inability to activate the cholesterol transporter ABCA1 in response to cholesterol loading. Their expression of the anti-inflammatory transcription factor Krüppel-like factor 2 was markedly reduced. Promoter studies revealed that IRF2BP2 is required for MEF2-dependent activation of Krüppel-like factor 2. Importantly, restoring Krüppel-like factor 2 in IRF2BP2-deficient macrophages attenuated M1 inflammatory and rescued M2 anti-inflammatory gene activation and improved the cholesterol efflux deficit by restoring ABCA1 activation in response to cholesterol loading. In a cohort of 1066 angiographic cases and 1011 controls, homozygous carriers of a deletion polymorphism (rs3045215) in the 3' untranslated region sequence of humanIRF2BP2 mRNA had a higher risk of coronary artery disease (recessive model, odds ratio [95% confidence interval]=1.560 [1.179-2.065], P=1.73E-03) and had lower IRF2BP2 (and Krüppel-like factor 2) protein levels in peripheral blood mononuclear cells. The effect of this deletion polymorphism to suppress protein expression was confirmed in luciferase reporter studies. CONCLUSION: Ablation of IRF2BP2 in macrophages worsens atherosclerosis in mice, and a deletion variant that lowers IRF2BP2 expression predisposes to coronary artery disease in humans.
Authors: Sarah K Baxter; Tom Walsh; Silvia Casadei; Mary M Eckert; Eric J Allenspach; David Hagin; Gesmar Segundo; Ming K Lee; Suleyman Gulsuner; Brian H Shirts; Kathleen E Sullivan; Michael D Keller; Troy R Torgerson; Mary-Claire King Journal: J Allergy Clin Immunol Date: 2021-04-20 Impact factor: 10.793
Authors: Gloria C Chi; Yongmei Liu; James W MacDonald; Lindsay M Reynolds; Daniel A Enquobahrie; Annette L Fitzpatrick; Kathleen F Kerr; Matthew J Budoff; Su-In Lee; David Siscovick; Joel D Kaufman Journal: Epigenetics Date: 2021-04-05 Impact factor: 4.528