Vitamin D Protects Human Endothelial Cells from H2O2 Oxidant Injury Through the Mek/Erk-Sirt1 Axis Activation

Abstract

Endothelium homeostasis alterations govern the pathogenesis of cardiovascular diseases. Several studies show that vitamins anti-oxidant proprieties rescue the endothelial functions adversely affected by oxidative stress in several diseases. We investigated the vitamin D anti-oxidant potential in human endothelial cells exposed to H2O2 oxidative stress. Vitamin D protected endothelial cells against H2O2 oxidative stress counteracting the superoxide anion generation, the apoptosis and blocking the extrinsic caspase cascade by positively controlling phospho-active ERKs level. MEKs/ERKs inhibitor U0126 reverted the vitamin D anti-oxidant effects. Characterizing the vitamin D downstream effector, we found that vitamin D up-regulated SirT-1 and reverted the SirT-1 down-regulation induced by H2O2. ERKs activation by vitamin D strictly correlated with SirT-1 protein accumulation since both MEKs/ERKs inhibition and ERK1/2 silencing decreased SIRT-1. SirT-1 inhibition by Sirtinol reverted the vitamin D anti-oxidant effects. Thus, vitamin D significantly reduced the endothelial malfunction and damage caused by oxidative stress, through the activation of MEKs/ERKs/SirT-1 axis.

Cyclic AMP Signaling Reduces Sirtuin 6 Expression in Non-small Cell Lung Cancer Cells by Promoting Ubiquitin-Proteasomal Degradation via Inhibition of the Raf-MEK-ERK (Raf/Mitogen-activated Extracellular Signal-regulated Kinase/Extracellular Signal-regulated Kinase) Pathway

“…These results agree with those published in previous reports showing that cAMP increases inhibitory Raf-1 phosphorylation at Ser-259 and reduces activating Raf-1 phosphorylation at Ser-338 in a PKA-dependent manner, thereby inducing ERK deactivation (33,34). ERK activates SIRT1 in chondrocytes (35) and induces SIRT1 expression in human endothelial cells (36); however, the effect of ERK on SIRT6 remains unknown. The present study showed that inhibiting the Raf-MEK-ERK pathway also reduces SIRT6 expression in lung cancer cells.…”

SirT1 and STAT3 protect retinal pigmented epithelium cells against oxidative stress

“…Bernier et al (22) reported negative regulation of STAT3 protein-mediated cellular respiration by SirT1 in murine embryonic fibroblast cells (21), and a previous study provided further support for these results (41). As previously demonstrated, pSTAT3 stimulated expression of the STAT3 gene [unphosphorylated STAT3 (U-STAT3)], which exerted persistent activity (42).…”

“…Cells were incubated with H 2 O 2 (50 µM) for 24 h. Subsequently, H 2 O 2 was detoxified by the addition of catalase (100,000 µl; Worthington Biochemical Corp., Lakewood, NJ, USA) at the end of the incubation (22). oxLDL (200 µg/ml) was added to other samples to induce pathological stress in ARPE-19 cells following 24 h treatment (23).…”

Dietary Intake of Vitamin D Is Related to Blood Levels of Advanced Glycation End Products during a Weight Loss Program in Obese Women

“…Recently, vitamin D has been indicated to exhibit anti-glycation [10,11,12] and anti-oxidation (oxidative stress is the final step of the Maillard reaction) effects [13,14]. In humans, there have been only two AGE studies using high-dosage vitamin D [10,12].…”