Inhibition of protein kinase Cβ prevents impaired endothelium-dependent vasodilation caused by hyperglycemia in humans

Joshua A. Beckman, Allison B. Goldfine, Mary Beth Gordon, Leslie A. Garrett, Mark A. Creager

Research output: Contribution to journalArticlepeer-review

250 Scopus citations


The bioavailability of nitric oxide is decreased in animal models and humans with diabetes mellitus. Hyperglycemia, in particular, attenuates endothelium-dependent vasodilation in healthy subjects. In vitro and in vivo animal studies implicate activation of protein kinase Cβ as an important mechanism whereby hyperglycemia decreases endothelium-derived nitric oxide. Accordingly, this study tested the hypothesis that inhibition of protein kinase Cβ would prevent impairment of endothelium-dependent vasodilation in healthy humans exposed to hyperglycemia. This study was a randomized, double-blind, placebo-controlled, crossover trial. Healthy subjects were treated with an orally active, selective, protein kinase Cβ inhibitor, LY333531, or matching placebo once a day for 7 days before vascular function testing. Forearm blood flow was measured using venous-occlusion, strain-gauge plethysmography. Endothelium-dependent vasodilation was measured via incremental brachial artery administration of methacholine chloride (0.3 to 10 μg/min) during euglycemia and after 6 hours of hyperglycemic clamp. The forearm blood flow dose-response curve to methacholine was significantly attenuated by hyperglycemia after placebo treatment (P=0.009 by ANOVA, euglycemia versus hyperglycemia) but not after treatment with LY333531. Inhibition of protein kinase Cβ prevents the reduction in endothelium-dependent vasodilation induced by acute hyperglycemia in healthy humans in vivo. These findings suggest that hyperglycemia impairs endothelial function, in part, via protein kinase Cβ activation.

Original languageEnglish (US)
Pages (from-to)107-111
Number of pages5
JournalCirculation research
Issue number1
StatePublished - Jan 11 2002
Externally publishedYes


  • Diabetes
  • Endothelium
  • Hyperglycemia
  • Nitric oxide
  • Protein kinase C

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine


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