Rosiglitazone stimulates nitric oxide synthesis in human aortic endothelial cells via AMP-activated protein kinase

James G. Boyle, Pamela J. Logan, Marie-Ann Ewart, James A. Reihill, Stuart A. Ritchie, John M. C. Connell, Stephen J. Cleland, Ian P. Salt (Lead / Corresponding author)

    Research output: Contribution to journalArticlepeer-review

    75 Citations (Scopus)

    Abstract

    The thiazolidinedione anti-diabetic drugs increase activation of endothelial nitric-oxide (NO) synthase by phosphorylation at Ser-1177 and increase NO bioavailability, yet the molecular mechanisms that underlie this remain poorly characterized. Several protein kinases, including AMP-activated protein kinase, have been demonstrated to phosphorylate endothelial NO synthase at Ser-1177. In the current study we determined the role of AMP-activated protein kinase in rosiglitazone-stimulated NO synthesis. Stimulation of human aortic endothelial cells with rosiglitazone resulted in the time- and dose-dependent stimulation of AMP-activated protein kinase activity and NO production with concomitant phosphorylation of endothelial NO synthase at Ser-1177. Rosiglitazone stimulated an increase in the ADP/ATP ratio in endothelial cells, and LKB1 was essential for rosiglitazone-stimulated AMPK activity in HeLa cells. Infection of endothelial cells with a virus encoding a dominant negative AMP-activated protein kinase mutant abrogated rosiglitazone-stimulated Ser-1177 phosphorylation and NO production. Furthermore, the stimulation of AMP-activated protein kinase and NO synthesis by rosiglitazone was unaffected by the peroxisome proliferator-activated receptor-? inhibitor GW9662. These studies demonstrate that rosiglitazone is able to acutely stimulate NO synthesis in cultured endothelial cells by an AMP-activated protein kinase-dependent mechanism, likely to be mediated by LKB1. © 2008 by The American Society for Biochemistry and Molecular Biology, Inc.
    Original languageEnglish
    Pages (from-to)11210-11217
    Number of pages8
    JournalJournal of Biological Chemistry
    Volume283
    Issue number17
    DOIs
    Publication statusPublished - 2008

    Keywords

    • Biochemistry
    • Blood vessel prostheses
    • Blood vessels
    • Chemical reactions
    • Cytology
    • Enzyme activity
    • Enzymes
    • Nitric oxide
    • Phosphorylation
    • Self assembly
    • Sugar (sucrose)
    • Activated protein kinases
    • Ampk activities
    • Bio availabilities
    • Dominant negatives
    • Hela cells
    • Human aortic endothelial cells
    • Molecular mechanisms
    • Peroxisome proliferator- activated receptors
    • Protein kinases
    • Rosiglitazone
    • Synthase
    • Thiazolidinedione
    • Endothelial cells
    • 2 chloro 5 nitrobenzanilide
    • adenosine diphosphate
    • adenosine triphosphate
    • endothelial nitric oxide synthase
    • hydroxymethylglutaryl coenzyme A reductase kinase
    • mutant protein
    • nitric oxide
    • pioglitazone
    • protein kinase LKB1
    • rosiglitazone
    • troglitazone
    • 2,4 thiazolidinedione derivative
    • AMP activated protein kinases
    • AMP-activated protein kinases
    • antidiabetic agent
    • multienzyme complex
    • nucleotide
    • protein serine threonine kinase
    • STK11 protein, human
    • amino acid sequence
    • aorta
    • artery endothelium
    • article
    • concentration response
    • controlled study
    • drug mechanism
    • endothelium cell
    • enzyme activity
    • enzyme phosphorylation
    • HeLa cell
    • human
    • human cell
    • human cell culture
    • priority journal
    • synthesis
    • biological model
    • cell culture
    • cell strain U937
    • chemistry
    • cytology
    • metabolism
    • phosphorylation
    • vascular endothelium
    • Aorta
    • Cells, Cultured
    • Endothelial Cells
    • Endothelium, Vascular
    • Hela Cells
    • Humans
    • Hypoglycemic Agents
    • Models, Biological
    • Multienzyme Complexes
    • Nitric Oxide
    • Nucleotides
    • Protein-Serine-Threonine Kinases
    • Thiazolidinediones
    • U937 Cells

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