Vitamin D Protects Human Endothelial Cells From Oxidative Stress Through the Autophagic and Survival Pathways

Context: Recently, vitamin D (VitD) has been recognized as increasingly importance in many cellular functions of several tissues and organs other than bone. In particular, VitD showed important beneficial effects in the cardiovascular system. Although the relationship among VitD, endothelium, and ca...

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Published in:The journal of clinical endocrinology and metabolism 2014-04, Vol.99 (4), p.1367-1374
Main Authors: Uberti, F, Lattuada, D, Morsanuto, V, Nava, U, Bolis, G, Vacca, G, Squarzanti, D. F, Cisari, C, Molinari, C
Format: Article
Language:English
Subjects:
Antioxidants - pharmacology
Autophagy - drug effects
Cell Survival - drug effects
Cells, Cultured
Cytoprotection
Endothelial Cells - drug effects
Endothelial Cells - physiology
Human Umbilical Vein Endothelial Cells - drug effects
Human Umbilical Vein Endothelial Cells - physiology
Humans
Hydrogen Peroxide - metabolism
Hydrogen Peroxide - pharmacology
Membrane Potential, Mitochondrial - drug effects
Nitric Oxide - metabolism
Oxidative Stress - drug effects
Reactive Oxygen Species - metabolism
Signal Transduction - drug effects
Vitamin D - pharmacology
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Summary:Context: Recently, vitamin D (VitD) has been recognized as increasingly importance in many cellular functions of several tissues and organs other than bone. In particular, VitD showed important beneficial effects in the cardiovascular system. Although the relationship among VitD, endothelium, and cardiovascular disease is well established, little is known about the antioxidant effect of VitD. Objective: Our objective was to study the intracellular pathways activated by VitD in cultured human umbilical vein endothelial cells undergoing oxidative stress. Design: Nitric oxide production, cell viability, reactive oxygen species, the mitochondrial permeability transition pore, membrane potential, and caspase-3 activity were measured during oxidative stress induced by administration of 200μM hydrogen peroxide for 20 minutes. Experiments were repeated in the presence of specific vitamin D receptor ligand ZK191784. Results: Pretreatment with VitD alone or in combination with ZK191784 is able to reduce the apoptosis-related gene expression, involving both intrinsic and extrinsic pathways. At the same time, it has been shown the activation of pro-autophagic beclin 1 and the phosphorylation of ERK1/2 and Akt, indicating a modulation between apoptosis and autophagy. Moreover, VitD alone or in combination with ZK191784 is able to prevent the loss of mitochondrial potential and the consequent cytochrome C release and caspase activation. Conclusions: The present study shows that VitD may prevent endothelial cell death through modulation of the interplay between apoptosis and autophagy. This effect is obtained by inhibiting superoxide anion generation, maintaining mitochondria function and cell viability, activating survival kinases, and inducing NO production.
ISSN:0021-972X
1945-7197
DOI:10.1210/jc.2013-2103