GLP-1-dependent and independent effects and molecular mechanisms of a dipeptidyl peptidase 4 inhibitor in vascular endothelial cells

Yunshan Hu, Hong Bin Liu, Richard Simpson, Anthony Edwin Dear

Research output: Contribution to journalArticleResearchpeer-review

28 Citations (Scopus)

Abstract

The potential atheroprotective effects of glucagon-like peptide-1 (GLP-1), long-acting GLP-1 analogues and inhibitors of the enzyme dipeptidyl peptidase 4 (DPP-4) are currently the subject of intense research. Recent evidence suggests the effects of DPP-IV inhibitors, may, in-part, be mediated by GLP-1 independent molecular mechanisms. In this report we demonstrate that treatment of human vascular endothelial cells with the DPP-IV inhibitor sitagliptin inhibited tumour necrosis factor alpha (TNFa) induction of plasminogen activator inhibitor type-1 (PAI-1), intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1) mRNA and protein expression and that this effect was observed to be both GLP-1-dependent and independent. Importantly we identify a molecular mechanism involving sitagliptin-mediated attenuation of TNFa-mediated induction of NF?B and orphan nuclear receptor NUR77 mRNA expression, also able to be reproduced, in part, independent of GLP-1. Taken together these observations may serve to provide a molecular explanation, involving transcriptional regulation of gene expression, for recent in vivo studies suggesting DPP-IV inhibitors may have novel, GLP-1 independent, effects in acting to attenuate endothelial cell dysfunction and atherogenesis.
Original languageEnglish
Pages (from-to)2273 - 2279
Number of pages7
JournalMolecular Biology Reports
Volume40
Issue number3
DOIs
Publication statusPublished - 2013

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