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

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An Erratum to this article was published on 28 December 2012

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 (TNFα) 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 TNFα-mediated induction of NFκB 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.

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Funding

This work was financially supported in-part by Merck, Sharpe and Dhome.

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Authors and Affiliations

  1. Eastern Clinical Research Unit, Translational Research Division, Department of Medicine, Australian Centre for Blood Diseases, Monash University, 89 Commercial Rd., Prahran 3181, Melbourne, VIC, Australia

    Hu Y, Liu HB & Dear AE

  2. Department of Medicine, Eastern Clinical School, Monash University, Level 2, 5 Arnold Street Box Hill 3128, Melbourne, VIC, Australia

    Simpson RW & Dear AE

  3. Department of Endocrinology, Eastern Health, Level 2, 5 Arnold Street Box Hill 3128, Melbourne, Australia

    Simpson RW

Authors
  1. Hu Y
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  2. Liu HB
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  3. Simpson RW
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  4. Dear AE
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Correspondence to Dear AE.

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Y, H., HB, L., RW, S. et al. GLP-1-dependent and independent effects and molecular mechanisms of a dipeptidyl peptidase 4 inhibitor in vascular endothelial cells. Mol Biol Rep 40, 2273–2279 (2013). https://doi.org/10.1007/s11033-012-2290-8

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  • DOI: https://doi.org/10.1007/s11033-012-2290-8

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