title: PKC-β activation inhibits IL-18-binding protein causing endothelial dysfunction and diabetic atherosclerosis.
abstract: OBJECTIVE
  Clinical observations showed a correlation between accelerated atherosclerosis in diabetes and high plasmatic level of IL-18, a pro-inflammatory cytokine. IL-18 enhances the production of inflammatory cytokines and cellular adhesion molecules contributing to atherosclerotic plaque formation and instability. Previous studies indicated that protein kinase C (PKC)-β inhibition prevented macrophage-induced cytokine expression involved in diabetic (DM) atherosclerotic plaque development. However, the role of PKC-β activation on IL-18/IL-18-binding protein (IL-18BP) pathway causing endothelial dysfunction and monocyte adhesion in diabetes has never been explored.
  
  
  RESULTS
  Apoe(-/-) mice were rendered DM and fed with western diet containing ruboxistaurin (RBX), a PKC-β inhibitor. After 20 weeks, atherosclerotic plaque composition was quantified. Compared with non-diabetic, DM mice exhibited elevated atherosclerotic plaque formation, cholestoryl ester content and macrophage infiltration, as well as reduced IL-18BP expression in the aorta which was prevented with RBX treatment. Endothelial cells (ECs) and macrophages were exposed to normal or high glucose (HG) levels with or without palmitate and recombinant IL-18 for 24 h. The combined HG and palmitate condition was required to increase IL-18 expression and secretion in macrophages, while it reduced IL-18BP expression in EC causing up-regulation of the vascular cell adhesion molecule (VCAM)-1 and monocyte adhesion. Elevated VCAM-1 expression and monocyte adherence were prevented by siRNA, RBX, and IL-18 neutralizing antibody.
  
  
  CONCLUSIONS
  Our study unrevealed a new mechanism by which PKC-β activation promotes EC dysfunction caused by the de-regulation of the IL-18/IL-18BP pathway, leading to increased VCAM-1 expression, monocyte/macrophage adhesion, and accelerated atherosclerotic plaque formation in diabetes.
authors: Research Center of the Centre Hospitalier Universitaire de Sherbrooke and Division of Endocrinology, Department of Medicine, Université de Sherbrooke, 3001 12e Avenue Nord, QC, Canada J1H 5N4.
authors: Marie-Claude
authors: MC
authors: Durpès
authors: Research Center of the Centre Hospitalier Universitaire de Sherbrooke and Division of Endocrinology, Department of Medicine, Université de Sherbrooke, 3001 12e Avenue Nord, QC, Canada J1H 5N4.
authors: Catherine
authors: C
authors: Morin
authors: Research Center of the Centre Hospitalier Universitaire de Sherbrooke and Division of Endocrinology, Department of Medicine, Université de Sherbrooke, 3001 12e Avenue Nord, QC, Canada J1H 5N4.
authors: Judith
authors: J
authors: Paquin-Veillet
authors: Research Center of the Centre Hospitalier Universitaire de Sherbrooke and Division of Endocrinology, Department of Medicine, Université de Sherbrooke, 3001 12e Avenue Nord, QC, Canada J1H 5N4.
authors: Raphaël
authors: R
authors: Beland
authors: Research Center of the Centre Hospitalier Universitaire de Sherbrooke and Division of Endocrinology, Department of Medicine, Université de Sherbrooke, 3001 12e Avenue Nord, QC, Canada J1H 5N4.
authors: Martin
authors: M
authors: Paré
authors: Research Center of the Centre Hospitalier Universitaire de Sherbrooke and Division of Endocrinology, Department of Medicine, Université de Sherbrooke, 3001 12e Avenue Nord, QC, Canada J1H 5N4.
authors: Marie-Odile
authors: MO
authors: Guimond
authors: Cardiometabolic Diseases and Complications of Diabetes, Lilly Research Laboratories, Indianapolis, IN, USA.
authors: Mark
authors: M
authors: Rekhter
authors: Research Division, Joslin Diabetes Center, Boston, MA, USA.
authors: George L
authors: GL
authors: King
authors: Research Center of the Centre Hospitalier Universitaire de Sherbrooke and Division of Endocrinology, Department of Medicine, Université de Sherbrooke, 3001 12e Avenue Nord, QC, Canada J1H 5N4 pedro.geraldes@usherbrooke.ca.
authors: Pedro
authors: P
authors: Geraldes
mesh_terms: D000818:Animals; D001057:Apolipoproteins E / Q000235:genetics; D050197:Atherosclerosis / Q000209:etiology / Q000235:genetics / Q000378:metabolism*; D048909:Diabetes Complications / Q000378:metabolism*; D003920:Diabetes Mellitus / Q000378:metabolism*; D042783:Endothelial Cells / Q000378:metabolism*; D020382:Interleukin-18 / Q000235:genetics / Q000378:metabolism*; D008264:Macrophages / Q000378:metabolism; D008297:Male; D051379:Mice; D009000:Monocytes / Q000378:metabolism; D064546:Protein Kinase C beta / Q000378:metabolism*; D019010:Vascular Cell Adhesion Molecule-1 / Q000235:genetics / Q000378:metabolism*
chemical_list: D001057:Apolipoproteins E; D020382:Interleukin-18; D019010:Vascular Cell Adhesion Molecule-1; D064546:Protein Kinase C beta
keywords: Atherosclerosis; Endothelial dysfunction; IL-18-binding protein; Protein kinase C beta