title: Inhibition of protein kinase Cbeta prevents impaired endothelium-dependent vasodilation caused by hyperglycemia in humans.
abstract: 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 Cbeta as an important mechanism whereby hyperglycemia decreases endothelium-derived nitric oxide. Accordingly, this study tested the hypothesis that inhibition of protein kinase Cbeta 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 Cbeta 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 microg/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 Cbeta 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 Cbeta activation.
authors.affiliation: Cardiovascular Division, Brigham and Women's Hospital, Joslin Diabetes Center, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Joshua A
authors.initials: JA
authors.lastname: Beckman
authors.forename: Allison B
authors.initials: AB
authors.lastname: Goldfine
authors.forename: Mary Beth
authors.initials: MB
authors.lastname: Gordon
authors.forename: Leslie A
authors.initials: LA
authors.lastname: Garrett
authors.forename: Mark A
authors.initials: MA
authors.lastname: Creager
mesh_terms: D000328:Adult; D001783:Blood Flow Velocity / Q000187:drug effects; D018592:Cross-Over Studies; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D004730:Endothelium, Vascular / Q000503:physiopathology*; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005260:Female; D005542:Forearm / Q000098:blood supply; D006801:Humans; D006943:Hyperglycemia / Q000503:physiopathology*; D007211:Indoles / Q000097:blood / Q000494:pharmacology*; D007527:Isoenzymes / Q000037:antagonists & inhibitors*; D008297:Male; D008301:Maleimides / Q000097:blood / Q000494:pharmacology*; D016210:Methacholine Chloride / Q000494:pharmacology; D011493:Protein Kinase C / Q000037:antagonists & inhibitors*; D064546:Protein Kinase C beta; D014664:Vasodilation / Q000187:drug effects*
chemical_list: D004791:Enzyme Inhibitors; D007211:Indoles; D007527:Isoenzymes; D008301:Maleimides; D016210:Methacholine Chloride; C099154:ruboxistaurin; D011493:Protein Kinase C; D064546:Protein Kinase C beta