Activation of Nrf2-Antioxidant Signaling by 1,25-Dihydroxycholecalciferol Prevents Leptin-Induced Oxidative Stress and Inflammation in Human Endothelial Cells

Abstract

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. The objective of this study was to determine the effects of 1,25-dihydroxycholecalciferol [1,25(OH)D] against leptin-induced oxidative stress and inflammation in human endothelial cells. 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 M) or supraphysiologic (10 M) concentrations of 1,25(OH)D and 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. Pretreatment of HUVECs with 1,25(OH)D prevented the leptin-induced increase in superoxide anion production ( < 0.05). Pretreatment with 1,25(OH)D further increased NRF2 translocation to the nucleus (by 3-fold; < 0.05) and increased mRNA expression of superoxide dismutase 2 (; by 2-fold), glutathione peroxidase (; by 3-fold), NAD(P)H dehydrogenase (quinone) 1 (; by 4-fold), and heme oxygenase 1 (; by 2-fold) ( < 0.05). Leptin doubled the translocation of NF-κB ( < 0.05) to the nucleus and increased ( < 0.05) the upregulation of vascular inflammatory mediators such as monocyte chemoattractant protein 1 (; by 1-fold), transforming growth factor β ( β by 1-fold), and vascular cell adhesion molecule 1 (; by 4-fold) ( < 0.05), which were prevented ( < 0.05) by pretreatment with 1,25(OH)D Protective effects of 1,25(OH)D were confirmed to be VDR dependent by using VDR siRNA. Pretreatment with 1,25(OH)D in the presence of a high concentration of leptin has a beneficial effect on HUVECs through the regulation of mediators of antioxidant activity and inflammation.

Implantation of VEGF‐functionalized cell‐free vascular grafts: regenerative and immunological response

“…Alternatively, VEGF may be coaxing MCs and Mϕs into differentiating to an EC fate. There is a growing body of literature suggesting that MCs may be capable of differentiating into EC‐like cells that express both MC/Mϕ markers and EC markers in vitro (56, 57, 73–82). In agreement, our results revealed that the lumen of SHV grafts contained cells that expressed both M2‐Mϕ and EC markers, but in subluminal areas they expressed only Mϕ markers.…”

Protective effects of novel derivatives of vitamin D3 and lumisterol against UVB-induced damage in human keratinocytes involve activation of Nrf2 and P53 defense mechanisms

“…It has previously been established that 1,25(OH) 2 D 3 and 20(OH)L 3 protect against ROS formation [34,35,45]. In this study we tested vitamin D 3 and lumisterol metabolites:…”

Vitamin D protects against particles‐caused lung injury through induction of autophagy in an Nrf2‐dependent manner

“…A large body of clinical evidence has demonstrated the prevalence and risks of VD deficiency in various chronic disease and toxins induced tissue damage . In addition, studies have documented that VD activates the Nrf2 signaling pathway to ameliorate leptin‐induced oxidative stress and inflammation in human endothelial cells and regulate TGFβ/Smad signaling pathway in a murine model of asthma, but the mechanism is not clear …”