Role for inducible cAMP early repressor in promoting pancreatic beta cell dysfunction evoked by oxidative stress in human and rat isletsReportar como inadecuado




Role for inducible cAMP early repressor in promoting pancreatic beta cell dysfunction evoked by oxidative stress in human and rat islets - Descarga este documento en PDF. Documentación en PDF para descargar gratis. Disponible también para leer online.

Diabetologia

, Volume 54, Issue 9, pp 2337–2346

First Online: 06 May 2011Received: 15 November 2010Accepted: 01 April 2011

Abstract

Aims-hypothesisPro-atherogenic and pro-oxidant, oxidised LDL trigger adverse effects on pancreatic beta cells, possibly contributing to diabetes progression. Because oxidised LDL diminish the expression of genes regulated by the inducible cAMP early repressor ICER, we investigated the involvement of this transcription factor and of oxidative stress in beta cell failure elicited by oxidised LDL.

MethodsIsolated human and rat islets, and insulin-secreting cells were cultured with human native or oxidised LDL or with hydrogen peroxide. The expression of genes was determined by quantitative real-time PCR and western blotting. Insulin secretion was monitored by EIA kit. Cell apoptosis was determined by scoring cells displaying pycnotic nuclei.

ResultsExposure of beta cell lines and islets to oxidised LDL, but not to native LDL raised the abundance of ICER. Induction of this repressor by the modified LDL compromised the expression of important beta cell genes, including insulin and anti-apoptotic islet brain 1, as well as of genes coding for key components of the secretory machinery. This led to hampering of insulin production and secretion, and of cell survival. Silencing of this transcription factor by RNA interference restored the expression of its target genes and alleviated beta cell dysfunction and death triggered by oxidised LDL. Induction of ICER was stimulated by oxidative stress, whereas antioxidant treatment with N-acetylcysteine or HDL prevented the rise of ICER elicited by oxidised LDL and restored beta cell functions.

Conclusions-interpretationInduction of ICER links oxidative stress to beta cell failure caused by oxidised LDL and can be effectively abrogated by antioxidant treatment.

KeywordsAntioxidant Apoptosis Diabetes HDL ICER Insulin Oxidative stress Oxidised LDL Pancreatic beta cells AbbreviationsCREcAMP responsive elements

CRElucLuciferase reporter construct driven by two CRE sequences linked upstream to a SV40 promoter

hGHHuman growth hormone

ICERInducible cAMP early repressor

JNKc-Jun amino terminal kinase

MAPKMitogen-activated protein kinase

NACN-Acetylcysteine

ROSReactive oxygen species

siSmall interfering

Electronic supplementary materialThe online version of this article doi:10.1007-s00125-011-2165-x contains supplementary material, which is available to authorised users.

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Autor: D. Favre - G. Niederhauser - D. Fahmi - V. Plaisance - S. Brajkovic - N. Beeler - F. Allagnat - J. A. Haefliger - R. Reg

Fuente: https://link.springer.com/







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