Circulation Research. 2002;90:107-111
Published online before print November 26, 2001, doi: 10.1161/hh0102.102359
Published online before print November 26, 2001, doi: 10.1161/hh0102.102359
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© 2002 American Heart Association, Inc.
Clinical Research |
Inhibition of Protein Kinase Cß Prevents Impaired Endothelium-Dependent Vasodilation Caused by Hyperglycemia in Humans
From the Cardiovascular Division (J.A.B., M.B.G., L.A.G., M.A.C.), Brigham and Women’s Hospital, and the Division of Cellular and Molecular Physiology (A.B.G.), Joslin Diabetes Center, Harvard Medical School, Boston, Mass.
Correspondence to Mark A. Creager, MD, Cardiovascular Division, Brigham and Women’s Hospital, 75 Francis St, Boston, MA 02115. E-mail mcreager{at}partners.org
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 Cß as an important mechanism whereby hyperglycemia decreases endothelium-derived nitric oxide. Accordingly, this study tested the hypothesis that inhibition of protein kinase Cß 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 Cß 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 Cß 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 Cß activation.
Key Words: protein kinase C • nitric oxide • hyperglycemia • endothelium • diabetes
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