Inhibition of protein kinase Cbeta does not improve endothelial function in type 2 diabetes.
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.
Beckman
Joshua A
JA
Brigham and Women's Hospital, 75 Francis Street, Boston, Massachusetts 02115, USA. jbeckman@partners.org
Goldfine
Allison B
AB
Goldin
Alison
A
Prsic
Adnan
A
Kim
Sora
S
Creager
Mark A
MA
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
D004791:Enzyme Inhibitors; D007211:Indoles; D008301:Maleimides; C099154:ruboxistaurin; D011493:Protein Kinase C; D064546:Protein Kinase C beta
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