Hyperglycemia promotes myelopoiesis and impairs the resolution of atherosclerosis

Cell Metab. 2013 May 7;17(5):695-708. doi: 10.1016/j.cmet.2013.04.001.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Atherosclerosis / metabolism
  • Atherosclerosis / pathology*
  • Bone Marrow / metabolism
  • Bone Marrow / pathology
  • Coronary Disease / metabolism
  • Coronary Disease / pathology
  • Cytokines / metabolism
  • Diabetes Mellitus, Experimental / metabolism
  • Diabetes Mellitus, Type 1 / metabolism
  • Diabetes Mellitus, Type 1 / pathology
  • Glucose / metabolism
  • Glycation End Products, Advanced / metabolism
  • Humans
  • Hyperglycemia / metabolism
  • Hyperglycemia / pathology*
  • Leukocytes / metabolism
  • Leukocytes / pathology
  • Leukocytosis / metabolism
  • Leukocytosis / pathology
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Monocytes / metabolism
  • Monocytes / pathology
  • Myeloid Progenitor Cells / metabolism
  • Myeloid Progenitor Cells / pathology
  • Myelopoiesis / physiology*
  • NF-kappa B / metabolism
  • Neutrophils / metabolism
  • Neutrophils / pathology
  • Receptor for Advanced Glycation End Products
  • Receptors, Immunologic / metabolism

Substances

  • Cytokines
  • Glycation End Products, Advanced
  • NF-kappa B
  • Receptor for Advanced Glycation End Products
  • Receptors, Immunologic
  • Glucose