title: Antagonistic effect of TNF-alpha and insulin on uncoupling protein 2 (UCP-2) expression and vascular damage.
abstract: BACKGROUND
  It has been reported that increased expression of UCP-2 in the vasculature may prevent the development of atherosclerosis in patients with increased production of reactive oxygen species, as in the diabetes, obesity or hypertension. Thus, a greater understanding in the modulation of UCP-2 could improve the atherosclerotic process. However, the effect of TNF-α or insulin modulating UCP-2 in the vascular wall is completely unknown. In this context, we propose to study new molecular mechanisms that help to explain whether the moderate hyperinsulinemia or lowering TNF-α levels might have a protective role against vascular damage mediated by UCP-2 expression levels.
  
  
  METHODS
  We analyzed the effect of insulin or oleic acid in presence or not of TNF-α on UCP-2 expression in murine endothelial and vascular smooth muscle cells. At this step, we wondered if some mechanisms studied in vitro could be of any relevance in vivo. We used the following experimental models: ApoE-/- mice under Western type diet for 2, 6, 12 or 18 weeks, BATIRKO mice under high-fat diet for 16 weeks and 52-week-old BATIRKO mice with o without anti-TNF-α antibody pre-treatment.
  
  
  RESULTS
  Firstly, we found that TNF-α pre-treatment reduced UCP-2 expression induced by insulin in vascular cells. Secondly, we observed a progressive reduction of UCP-2 levels together with an increase of lipid depots and lesion area in aorta from ApoE-/- mice. In vivo, we also observed that moderate hyperinsulinemic obese BATIRKO mice have lower TNF-α and ROS levels and increased UCP-2 expression levels within the aorta, lower lipid accumulation, vascular dysfunction and macrovascular damage. We also observed that the anti-TNF-α antibody pre-treatment impaired the loss of UCP-2 expression within the aorta and relieved vascular damage observed in 52-week-old BATIRKO mice. Finally, we observed that the pretreatment with iNOS inhibitor prevented UCP-2 reduction induced by TNF-α in vascular cells. Moreover, iNOS levels are augmented in aorta from mice with lower UCP-2 levels and higher TNF-α levels.
  
  
  CONCLUSIONS
  Our data suggest that moderate hyperinsulinemia in response to insulin resistance or lowering of TNF-α levels within the aorta attenuates vascular damage, this protective effect being mediated by UCP-2 expression levels through iNOS.
authors: Almudena
authors: A
authors: Gómez-Hernández
authors: Liliana
authors: L
authors: Perdomo
authors: Natalia
authors: N
authors: de las Heras
authors: Nuria
authors: N
authors: Beneit
authors: Oscar
authors: O
authors: Escribano
authors: Yolanda F
authors: YF
authors: Otero
authors: Carlos
authors: C
authors: Guillén
authors: Sabela
authors: S
authors: Díaz-Castroverde
authors: Beatriz
authors: B
authors: Gozalbo-López
authors: Victoria
authors: V
authors: Cachofeiro
authors: Vicente
authors: V
authors: Lahera
authors: Manuel
authors: M
authors: Benito
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D005786:Gene Expression Regulation; D007328:Insulin / Q000494:pharmacology*; D007473:Ion Channels / Q000037:antagonists & inhibitors* / Q000096:biosynthesis*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D024101:Mitochondrial Proteins / Q000037:antagonists & inhibitors* / Q000096:biosynthesis*; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D032389:Myocytes, Smooth Muscle / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*; D000071246:Uncoupling Protein 2
chemical_list: D007328:Insulin; D007473:Ion Channels; D024101:Mitochondrial Proteins; D014409:Tumor Necrosis Factor-alpha; C000604390:Ucp2 protein, mouse; D000071246:Uncoupling Protein 2