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Peroxisome proliferator-activated receptor-β activation restores the high glucose-induced impairment of insulin signaling in endothelial cells.
MedLine Citation:
PMID:  24527778     Owner:  NLM     Status:  Publisher    
BACKGROUND AND PURPOSE: We analyzed the effects of the peroxisome proliferator-activated receptor β/δ (PPAR-β) agonists, GW0742 and L165041, on the impaired insulin signaling induced by high glucose in human umbilical vein endothelial cells (HUVECs) and aorta and mesenteric arteries from diabetic rats.
EXPERIMENTAL APPROACH: Insulin-stimulated NO production, Akt-Ser473 and eNOS-Ser1177 phosphorylation, and reactive oxygen species (ROS) production were studied in HUVECs incubated in low or high glucose medium. Insulin-stimulated relaxations and protein phosphorylation in vessel from streptozotocin (STZ)-induced diabetic rats were also analyzed.
KEY RESULTS: HUVECs incubated in high glucose medium showed a significant reduction of the insulin-stimulated production of NO. High glucose also reduced insulin-induced Akt-Ser473 and eNOS-Ser1177 phosphorylation, increased IRS-1-Ser636 and ERK1/2-Thr183-Tyr185 phosphorylation and increased ROS production. The coincubation with the PPAR-β agonists GW0742 or L165041 prevented all the effects induced by high glucose. In turn, the effects induced by the agonists were suppressed when HUVEC were also incubated with the PPAR-β antagonist GSK0660, the piruvate dehydrogenase kinase (PDK)-4 inhibitor dichloroacetate or after knockdown of both PPAR-β and PDK4 with siRNA. The ERK1/2 inhibitor PD98059, the ROS scavenger catalase, the inhibitor of complex II thenoyltrifluoroacetone or the uncoupler of oxidative phosphorylation, carbonyl cyanide m-chlorophenylhydrazone also prevented glucose-induced insulin resistance. In STZ diabetic rats, oral GW0742 also improved insulin signaling and the impaired NO-mediated vascular relaxation.
CONCLUSIONS AND IMPLICATIONS: PPAR-β activation in vitro and in vivo restores the endothelial function, preserving the insulin-Akt-eNOS pathway impaired by high glucose, at least in part, through PDK4 activation.
A M Quintela; R Jiménez; L Piqueras; M Gómez-Guzmán; J Haro; M J Zarzuelo; A Cogolludo; M J Sanz; M Toral; M Romero; F Pérez-Vizcaíno; J Duarte
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Publication Detail:
Type:  JOURNAL ARTICLE     Date:  2014-2-16
Journal Detail:
Title:  British journal of pharmacology     Volume:  -     ISSN:  1476-5381     ISO Abbreviation:  Br. J. Pharmacol.     Publication Date:  2014 Feb 
Date Detail:
Created Date:  2014-2-17     Completed Date:  -     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  7502536     Medline TA:  Br J Pharmacol     Country:  -    
Other Details:
Languages:  ENG     Pagination:  -     Citation Subset:  -    
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This article is protected by copyright. All rights reserved.
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