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

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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.

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Authors and Affiliations

  1. Department of Internal Medicine and Public Health, University of L’Aquila, L’Aquila, Italy

    Lorella Polidoro, G. Properzi & C. Ferri

  2. Department of Experimental Medicine, Division of Radiotherapy and Radiobiology, University of L’Aquila, L’Aquila, Italy

    F. Marampon, G. L. Gravina, C. Festuccia & E. Di Cesare

  3. Department of Experimental Medicine, University of L’Aquila, L’Aquila, Italy

    L. Scarsella, C. Ciccarelli & B. M. Zani

Authors
  1. Lorella Polidoro
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  2. G. Properzi
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  3. F. Marampon
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  4. G. L. Gravina
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  5. C. Festuccia
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  6. E. Di Cesare
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  7. L. Scarsella
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  8. C. Ciccarelli
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  9. B. M. Zani
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  10. C. Ferri
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Correspondence to Lorella Polidoro.

Additional information

L. Polidoro and G. Properzi contributed equally to this work.

Clinical Relevance of the Manuscript

Oxidative stress is believed to play a crucial role in the initiation and progression of several cardiovascular diseases. The vascular endothelium, which regulates the passage of macromolecules and circulating cells from blood to tissues, is a major target of oxidant stress, playing a critical role in the pathophysiology of several vascular disorders. Use of antioxidants in most clinical trials demonstrated that this treatment prevents and retards the progression of many diseases. Supplemental vitamin D significantly reduces all-cause mortality. Many evidences suggested that vitamin D play an essential role in the endothelium homeostasis and its deficiency contributes to cardiovascular diseases. Knowledge of the molecular mechanisms by which antioxidants act would be useful to both the understanding of the oxidative stress pathways that bring to the endothelial dysfunction and to the identification of possible new therapeutic strategies. The mechanisms by which vitamin D acts are largely unknown. We investigated the antioxidant potential of vitamin D using the human umbilical vein endothelial cell (HUVEC), an important model of the human endothelium that is widely used in in vitro vascular research. For the first time we show that Vitamin D counteracts the oxidative stress through the activation of MEKs/ERKs/Sirt-1 molecular axis. Increasing scientific evidences point attention on the cardio-protective effects of resveratrol, an activator of SIRT-1. Thus, our data on the role of MEKs/ERKs/Sirt-1 axis in endothelial malfunctions stresses the relevance of developing combined therapies to sustain ERK and SIRT activation in a “Signal Transduction-Based” manner for pre- and clinical studies.

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Polidoro, L., Properzi, G., Marampon, F. et al. Vitamin D Protects Human Endothelial Cells from H2O2 Oxidant Injury Through the Mek/Erk-Sirt1 Axis Activation. J. of Cardiovasc. Trans. Res. 6, 221–231 (2013). https://doi.org/10.1007/s12265-012-9436-x

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