title: Induction of vascular insulin resistance and endothelin-1 expression and acceleration of atherosclerosis by the overexpression of protein kinase C-β isoform in the endothelium.
abstract: BACKGROUND
  Loss of insulin action in the endothelium can cause endothelial dysfunction and atherosclerosis. Hyperglycemia and elevated fatty acids induced by diabetes mellitus can activate protein kinase C-β isoforms and selectively inhibit insulin signaling via phosphatidylinositol 3-kinase/Akt pathway to inhibit the activation of endothelial nitric oxide synthase and metabolic actions.
  
  
  OBJECTIVE
  To demonstrate that overexpressing protein kinase C-β2 isoform in endothelial cells can cause selective insulin resistance and exacerbate atherosclerosis in the aorta.
  
  
  RESULTS
  Protein kinase C-β2 isoform was overexpressed in endothelial cells using a promoter of vascular endothelial cell cadherin. These mice were cross-bred with apoE-/- mice [Tg (Prkcb)apoE-/-]. On a Western diet, Tg(Prkcb)apoE-/- and apoE-/- mice did not differ in systemic insulin sensitivity, glucose tolerance, plasma lipid, or blood pressure. Insulin action in endothelial cells and femoral artery from Tg(Prkcb)apoE-/- mice was impaired by ≈40% with respect to Akt/endothelial nitric oxide synthase activation, and leukocyte-endothelial cell binding increased in cultured lung endothelial cells from Tg(Prkcb)apoE-/- mice compared with that from apoE-/- mice. Basal and angiotensin-stimulated big endothelin-1 levels were elevated in Tg(Prkcb)apoE-/- mice compared with apoE-/- mice. The severity of atherosclerosis in the aorta from Tg(Prkcb)apoE-/- mice increased by ≈70% as measured by en face fat staining and plaque content of the number of smooth muscle cells, macrophages, and extracellular matrix.
  
  
  CONCLUSIONS
  Specific protein kinase C-β2 activation in the endothelial cells caused dysfunction and accelerated atherosclerosis because of loss of insulin-stimulated Akt/endothelial nitric oxide synthase activation and angiotensin-induced increases in endothelin-1 expression.
authors.affiliation: Dianne Nunnally Hoppes Laboratory for Diabetes Complications, Section of Vascular Cell Biology, Joslin Diabetes Center, Harvard Medical School, Boston, Massachusetts 02215, USA.
authors.forename: Qian
authors.initials: Q
authors.lastname: Li
authors.forename: Kyoungmin
authors.initials: K
authors.lastname: Park
authors.forename: Chenzhong
authors.initials: C
authors.lastname: Li
authors.forename: Christian
authors.initials: C
authors.lastname: Rask-Madsen
authors.forename: Akira
authors.initials: A
authors.lastname: Mima
authors.forename: Weier
authors.initials: W
authors.lastname: Qi
authors.forename: Koji
authors.initials: K
authors.lastname: Mizutani
authors.forename: Paul
authors.initials: P
authors.lastname: Huang
authors.forename: George L
authors.initials: GL
authors.lastname: King
mesh_terms: D000818:Animals; D001011:Aorta / Q000473:pathology / Q000503:physiopathology; D001057:Apolipoproteins E / Q000172:deficiency / Q000235:genetics / Q000502:physiology; D050197:Atherosclerosis / Q000473:pathology / Q000503:physiopathology*; D004195:Disease Models, Animal; D019332:Endothelin-1 / Q000235:genetics / Q000502:physiology*; D004730:Endothelium, Vascular / Q000473:pathology / Q000503:physiopathology*; D005260:Female; D007333:Insulin Resistance / Q000502:physiology*; D007527:Isoenzymes / Q000235:genetics / Q000502:physiology; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D052250:Nitric Oxide Synthase Type III / Q000502:physiology; D064546:Protein Kinase C beta / Q000235:genetics / Q000502:physiology*; D051057:Proto-Oncogene Proteins c-akt / Q000502:physiology; D015854:Up-Regulation / Q000502:physiology*; D019010:Vascular Cell Adhesion Molecule-1 / Q000502:physiology
chemical_list: D001057:Apolipoproteins E; D019332:Endothelin-1; D007527:Isoenzymes; D019010:Vascular Cell Adhesion Molecule-1; D052250:Nitric Oxide Synthase Type III; D051057:Proto-Oncogene Proteins c-akt; D064546:Protein Kinase C beta
keywords: atherosclerosis; endothelium; insulin resistance; protein kinase C