title: Hyperglycemia promotes myelopoiesis and impairs the resolution of atherosclerosis.
abstract: Diabetes is a major risk factor for atherosclerosis. Although atherosclerosis is initiated by deposition of cholesterol-rich lipoproteins in the artery wall, the entry of inflammatory leukocytes into lesions fuels disease progression and impairs resolution. We show that diabetic mice have increased numbers of circulating neutrophils and Ly6-C(hi) monocytes, reflecting hyperglycemia-induced proliferation and expansion of bone marrow myeloid progenitors and release of monocytes into the circulation. Increased neutrophil production of S100A8/S100A9, and its subsequent interaction with the receptor for advanced glycation end products on common myeloid progenitor cells, leads to enhanced myelopoiesis. Treatment of hyperglycemia reduces monocytosis, entry of monocytes into atherosclerotic lesions, and promotes regression. In patients with type 1 diabetes, plasma S100A8/S100A9 levels correlate with leukocyte counts and coronary artery disease. Thus, hyperglycemia drives myelopoiesis and promotes atherogenesis in diabetes.
authors.affiliation: Division of Preventive Medicine and Nutrition, Department of Medicine, Columbia University, New York, NY 10032, USA.
authors.forename: Prabhakara R
authors.initials: PR
authors.lastname: Nagareddy
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Murphy
authors.forename: Roslynn A
authors.initials: RA
authors.lastname: Stirzaker
authors.forename: Yunying
authors.initials: Y
authors.lastname: Hu
authors.forename: Shiquing
authors.initials: S
authors.lastname: Yu
authors.forename: Rachel G
authors.initials: RG
authors.lastname: Miller
authors.forename: Bhama
authors.initials: B
authors.lastname: Ramkhelawon
authors.forename: Emilie
authors.initials: E
authors.lastname: Distel
authors.forename: Marit
authors.initials: M
authors.lastname: Westerterp
authors.forename: Li-Shin
authors.initials: LS
authors.lastname: Huang
authors.forename: Ann Marie
authors.initials: AM
authors.lastname: Schmidt
authors.forename: Trevor J
authors.initials: TJ
authors.lastname: Orchard
authors.forename: Edward A
authors.initials: EA
authors.lastname: Fisher
authors.forename: Alan R
authors.initials: AR
authors.lastname: Tall
authors.forename: Ira J
authors.initials: IJ
authors.lastname: Goldberg
mesh_terms: D000818:Animals; D050197:Atherosclerosis / Q000378:metabolism / Q000473:pathology*; D001853:Bone Marrow / Q000378:metabolism / Q000473:pathology; D003327:Coronary Disease / Q000378:metabolism / Q000473:pathology; D016207:Cytokines / Q000378:metabolism; D003921:Diabetes Mellitus, Experimental / Q000378:metabolism; D003922:Diabetes Mellitus, Type 1 / Q000378:metabolism / Q000473:pathology; D005947:Glucose / Q000378:metabolism; D017127:Glycation End Products, Advanced / Q000378:metabolism; D006801:Humans; D006943:Hyperglycemia / Q000378:metabolism / Q000473:pathology*; D007962:Leukocytes / Q000378:metabolism / Q000473:pathology; D007964:Leukocytosis / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009000:Monocytes / Q000378:metabolism / Q000473:pathology; D023461:Myeloid Progenitor Cells / Q000378:metabolism / Q000473:pathology; D038042:Myelopoiesis / Q000502:physiology*; D016328:NF-kappa B / Q000378:metabolism; D009504:Neutrophils / Q000378:metabolism / Q000473:pathology; D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic / Q000378:metabolism
chemical_list: D016207:Cytokines; D017127:Glycation End Products, Advanced; D016328:NF-kappa B; D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic; D005947:Glucose