title: Inhibition of protein kinase Cbeta does not improve endothelial function in type 2 diabetes.
abstract: BACKGROUND
  Antagonism of protein kinase Cbeta (PKCbeta) restores endothelial function in experimental models of diabetes and prevents vascular dysfunction in response to hyperglycemia in healthy humans.
  
  
  OBJECTIVE
  We tested the hypothesis that PKCbeta antagonism would improve vascular function in subjects with type 2 diabetes compared with healthy control subjects.
  
  
  METHODS
  The effect of PKCbeta was evaluated in a randomized, placebo-controlled, double-blinded crossover trial.
  
  
  METHODS
  The study was performed in the outpatient setting of a university medical center.
  
  
  METHODS
  Thirteen subjects with type 2 diabetes without evidence of cardiovascular disease and 15 healthy control subjects were recruited via newspaper advertisement.
  
  
  METHODS
  Subjects underwent a randomized, double-blind, crossover, placebo-controlled trial of the selective PKCbeta antagonist ruboxistaurin mesylate. Subjects received each treatment for 14 d.
  
  
  METHODS
  Endothelium-dependent and endothelium-independent vasodilation of forearm resistance vessels was measured with mercury-in-silastic, strain-gauge plethysmography during intraarterial administration of methacholine chloride and verapamil, respectively. Markers of inflammation, fibrinolysis, endothelial damage, and oxidative stress were measured after each treatment.
  
  
  RESULTS
  Endothelium-dependent vasodilation of forearm resistance vessels was attenuated in diabetic subjects when compared with healthy subjects (P=0.001). Endothelium-independent vasodilation did not differ between groups (P value not significant). Ruboxistaurin did not significantly change endothelium-dependent or endothelium-independent vasodilation or blood-based markers of inflammation, fibrinolysis, endothelial damage, and oxidative stress in either diabetic or healthy subjects.
  
  
  CONCLUSIONS
  Endothelial dysfunction of forearm resistance vessels was not improved by 2 wk of selective PKCbeta inhibition in patients with diabetes. These results suggest that PKCbeta does not contribute significantly to vascular dysfunction in otherwise healthy patients with type 2 diabetes.
authors.affiliation: Brigham and Women's Hospital, 75 Francis Street, Boston, Massachusetts 02115, USA. jbeckman@partners.org
authors.forename: Joshua A
authors.initials: JA
authors.lastname: Beckman
authors.forename: Allison B
authors.initials: AB
authors.lastname: Goldfine
authors.forename: Alison
authors.initials: A
authors.lastname: Goldin
authors.forename: Adnan
authors.initials: A
authors.lastname: Prsic
authors.forename: Sora
authors.initials: S
authors.lastname: Kim
authors.forename: Mark A
authors.initials: MA
authors.lastname: Creager
mesh_terms: D000328:Adult; D000368:Aged; D000704:Analysis of Variance; D018592:Cross-Over Studies; D003924:Diabetes Mellitus, Type 2 / Q000503:physiopathology*; D004311:Double-Blind Method; D004730:Endothelium, Vascular / Q000187:drug effects / Q000503:physiopathology*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D005542:Forearm / Q000098:blood supply / Q000503:physiopathology; D006801:Humans; D007211:Indoles / Q000494:pharmacology*; D008297:Male; D008301:Maleimides / Q000494:pharmacology*; D008875:Middle Aged; D018384:Oxidative Stress / Q000187:drug effects; D011493:Protein Kinase C / Q000037:antagonists & inhibitors*; D064546:Protein Kinase C beta; D014664:Vasodilation / Q000187:drug effects
chemical_list: D004791:Enzyme Inhibitors; D007211:Indoles; D008301:Maleimides; C099154:ruboxistaurin; D011493:Protein Kinase C; D064546:Protein Kinase C beta
references.citation: Diabetologia. 2003 Apr;46(4):514-9
references.pmid: 12739024
references.citation: Cardiovasc Drugs Ther. 2009 Feb;23(1):17-24
references.pmid: 18949545
references.citation: J Am Soc Echocardiogr. 2006 Dec;19(12):1471-81
references.pmid: 17138032
references.citation: Diabetes Care. 2007 Apr;30(4):896-902
references.pmid: 17392551
references.citation: Diabetes. 2002 Oct;51(10):3049-54
references.pmid: 12351446
references.citation: J Pharmacol Exp Ther. 2006 Oct;319(1):199-207
references.pmid: 16861398
references.citation: J Am Coll Cardiol. 1996 Mar 1;27(3):567-74
references.pmid: 8606266
references.citation: Am J Physiol Heart Circ Physiol. 2004 Feb;286(2):H492-7
references.pmid: 14715497
references.citation: Biochem J. 1998 Jun 1;332 ( Pt 2):281-92
references.pmid: 9601053
references.citation: Clin Ther. 2005 Aug;27(8):1164-80
references.pmid: 16199243
references.citation: Circ Res. 2002 Jan 11;90(1):107-11
references.pmid: 11786526
references.citation: Diabetes. 2000 Nov;49(11):1939-45
references.pmid: 11078463
references.citation: Proc Natl Acad Sci U S A. 1992 Nov 15;89(22):11059-63
references.pmid: 1438315
references.citation: Clin Sci (Lond). 2002 Sep;103(3):311-21
references.pmid: 12193157
references.citation: Diabetes Care. 2005 Nov;28(11):2686-90
references.pmid: 16249540
references.citation: Arch Ophthalmol. 2007 Mar;125(3):318-24
references.pmid: 17353401
references.citation: JAMA. 2002 May 15;287(19):2570-81
references.pmid: 12020339
references.citation: Diabetes. 2006 Mar;55(3):691-8
references.pmid: 16505232
references.citation: Ophthalmology. 2006 Dec;113(12):2221-30
references.pmid: 16989901