title: Activation of Nrf2-Antioxidant Signaling by 1,25-Dihydroxycholecalciferol Prevents Leptin-Induced Oxidative Stress and Inflammation in Human Endothelial Cells.
abstract: Background:Obesity is associated with hyperleptinemia and endothelial dysfunction. Hyperleptinemia has been reported to induce both oxidative stress and inflammation by increasing reactive oxygen species production.Objective:The objective of this study was to determine the effects of 1,25-dihydroxycholecalciferol [1,25(OH)2D3] against leptin-induced oxidative stress and inflammation in human endothelial cells.Methods:Small interfering RNA (siRNA) were used to knock down the expression of vitamin D receptor (VDR) in human umbilical vein endothelial cells (HUVECs). HUVECs were pretreated for 4 h with physiologic (10-10M) or supraphysiologic (10-7M) concentrations of 1,25(OH)2D3and exposed to leptin (10 ng/mL). Superoxide anion production and translocation of nuclear factor (erythroid-derived 2)-like 2 (NRF2) and nuclear transcription factor κB (NF-κB) subunit p65 to the nucleus and the activation of their target genes were quantified.Results:Pretreatment of HUVECs with 1,25(OH)2D3prevented the leptin-induced increase in superoxide anion production (P< 0.05). Pretreatment with 1,25(OH)2D3further increased NRF2 translocation to the nucleus (by 3-fold;P< 0.05) and increased mRNA expression of superoxide dismutase 2 (SOD2; by 2-fold), glutathione peroxidase (GPX; by 3-fold), NAD(P)H dehydrogenase (quinone) 1 (NQO1; by 4-fold), and heme oxygenase 1 (HMOX1; by 2-fold) (P< 0.05). Leptin doubled the translocation of NF-κB (P< 0.05) to the nucleus and increased (P< 0.05) the upregulation of vascular inflammatory mediators such as monocyte chemoattractant protein 1 (MCP1; by 1-fold), transforming growth factor β (TGFβ by 1-fold), and vascular cell adhesion molecule 1 (VCAM1; by 4-fold) (P< 0.05), which were prevented (P< 0.05) by pretreatment with 1,25(OH)2D3Protective effects of 1,25(OH)2D3were confirmed to be VDR dependent by using VDR siRNA.Conclusion:Pretreatment with 1,25(OH)2D3in the presence of a high concentration of leptin has a beneficial effect on HUVECs through the regulation of mediators of antioxidant activity and inflammation.
authors.affiliation: Departments of Basic and Experimental Nutrition and.
authors.forename: Thaisa M
authors.initials: TM
authors.lastname: Teixeira
authors.affiliation: Departments of Basic and Experimental Nutrition and.
authors.forename: Danielly C
authors.initials: DC
authors.lastname: da Costa
authors.affiliation: Pharmacology, Rio de Janeiro State University, Rio de Janeiro, Brazil; and.
authors.forename: Angela C
authors.initials: AC
authors.lastname: Resende
authors.affiliation: University of Lyon, CarMeN Laboratory, Villeurbanne, France.
authors.forename: Christophe O
authors.initials: CO
authors.lastname: Soulage
authors.affiliation: Departments of Basic and Experimental Nutrition and.
authors.forename: Flavia F
authors.initials: FF
authors.lastname: Bezerra
authors.affiliation: Departments of Basic and Experimental Nutrition and juliobd@gmail.com.
authors.forename: Julio B
authors.initials: JB
authors.lastname: Daleprane
mesh_terms: D000975:Antioxidants; D002117:Calcitriol / Q000008:administration & dosage / Q000494:pharmacology*; D002470:Cell Survival; D042783:Endothelial Cells / Q000378:metabolism*; D005786:Gene Expression Regulation / Q000502:physiology; D006801:Humans; D007249:Inflammation / Q000139:chemically induced* / Q000378:metabolism; D020738:Leptin / Q000494:pharmacology*; D051267:NF-E2-Related Factor 2 / Q000235:genetics / Q000378:metabolism*; D018384:Oxidative Stress / Q000187:drug effects* / Q000502:physiology; D015398:Signal Transduction; D013481:Superoxides / Q000378:metabolism
chemical_list: D000975:Antioxidants; D020738:Leptin; D051267:NF-E2-Related Factor 2; C495635:NFE2L2 protein, human; D013481:Superoxides; D002117:Calcitriol
keywords: endothelium; inflammation; leptin; oxidative stress; vitamin D