title: PKCβ promotes vascular inflammation and acceleration of atherosclerosis in diabetic ApoE null mice.
abstract: OBJECTIVE
  Subjects with diabetes mellitus are at high risk for developing atherosclerosis through a variety of mechanisms. Because the metabolism of glucose results in production of activators of protein kinase C (PKC)β, it was logical to investigate the role of PKCβ in modulation of atherosclerosis in diabetes mellitus.
  
  
  RESULTS
  ApoE(-/-) and PKCβ(-/-)/ApoE(-/-) mice were rendered diabetic with streptozotocin. Quantification of atherosclerosis, gene expression profiling, or analysis of signaling molecules was performed on aortic sinus or aortas from diabetic mice. Diabetes mellitus-accelerated atherosclerosis increased the level of phosphorylated extracellular signal-regulated kinase 1/2 and Jun-N-terminus kinase mitogen-activated protein kinases and augmented vascular expression of inflammatory mediators, as well as increased monocyte/macrophage infiltration and CD11c(+) cells accumulation in diabetic ApoE(-/-) mice, processes that were diminished in diabetic PKCβ(-/-)/ApoE(-/-) mice. In addition, pharmacological inhibition of PKCβ reduced atherosclerotic lesion size in diabetic ApoE(-/-) mice. In vitro, the inhibitors of PKCβ and extracellular signal-regulated kinase 1/2, as well as small interfering RNA to Egr-1, significantly decreased high-glucose-induced expression of CD11c (integrin, alpha X 9 complement component 3 receptor 4 subunit]), chemokine (C-C motif) ligand 2, and interleukin-1β in U937 macrophages.
  
  
  CONCLUSIONS
  These data link enhanced activation of PKCβ to accelerated diabetic atherosclerosis via a mechanism that includes modulation of gene transcription and signal transduction in the vascular wall, processes that contribute to acceleration of vascular inflammation and atherosclerosis in diabetes mellitus. Our results uncover a novel role for PKCβ in modulating CD11c expression and inflammatory response of macrophages in the development of diabetic atherosclerosis. These findings support PKCβ activation as a potential therapeutic target for prevention and treatment of diabetic atherosclerosis.
authors.affiliation: Diabetes Research Program, Division of Endocrinology, Department of Medicine, NYU School of Medicine, New York, NY 10016, USA.
authors.forename: Linghua
authors.initials: L
authors.lastname: Kong
authors.forename: Xiaoping
authors.initials: X
authors.lastname: Shen
authors.forename: Lili
authors.initials: L
authors.lastname: Lin
authors.forename: Michael
authors.initials: M
authors.lastname: Leitges
authors.forename: Rosa
authors.initials: R
authors.lastname: Rosario
authors.forename: Yu Shan
authors.initials: YS
authors.lastname: Zou
authors.forename: Shi Fang
authors.initials: SF
authors.lastname: Yan
mesh_terms: D000818:Animals; D001025:Aortitis / Q000276:immunology; D001057:Apolipoproteins E / Q000235:genetics / Q000276:immunology*; D050197:Atherosclerosis / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D039521:CD11c Antigen / Q000378:metabolism; D003921:Diabetes Mellitus, Experimental / Q000276:immunology*; D003925:Diabetic Angiopathies / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D004195:Disease Models, Animal; D015870:Gene Expression / Q000276:immunology; D006801:Humans; D006943:Hyperglycemia / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D006949:Hyperlipidemias / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D008264:Macrophages / Q000276:immunology; D051379:Mice; D018345:Mice, Knockout; D009000:Monocytes / Q000276:immunology; D011493:Protein Kinase C / Q000235:genetics / Q000276:immunology*; D064546:Protein Kinase C beta; D015398:Signal Transduction / Q000276:immunology; D020298:U937 Cells; D014657:Vasculitis / Q000235:genetics / Q000276:immunology* / Q000378:metabolism
chemical_list: D001057:Apolipoproteins E; D039521:CD11c Antigen; D011493:Protein Kinase C; D064546:Protein Kinase C beta
keywords: PKCβ; antigens, CD11c; atherosclerosis; diabetes mellitus; inflammation