Vitamin D Protects Human Endothelial Cells from H2O2 Oxidant Injury Through the Mek/Erk-Sirt1 Axis Activation
Vitamin D Protects Human Endothelial Cells from H2O2 Oxidant Injury Through the Mek/Erk-Sirt1 Axis Activation
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DOI：
10.1007/s12265-012-9436-x
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发表时间：
2013-04-01
影响因子：
3.4
通讯作者：
Ferri, C.
中科院分区：
文献类型：
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作者：
Polidoro, Lorella;Properzi, G.;Ferri, C.
内皮细胞稳态的改变控制着心血管疾病的发病机制。几项研究表明，维生素抗氧化特性拯救了几种疾病中受氧化应激不利影响的内皮功能。我们研究了维生素D在暴露于H2 O2氧化应激的人内皮细胞中的抗氧化潜力。维生素D通过积极调控磷酸化活性ERK的水平，保护内皮细胞免受H2 O2氧化应激，对抗超氧阴离子的产生，抑制细胞凋亡，阻断外源性caspase级联反应。MEK/ERK抑制剂U 0126逆转了维生素D的抗氧化作用。表征维生素D的下游效应，我们发现，维生素D上调SirT-1和逆转SirT-1下调诱导H2 O2。维生素D激活ERK与SIRT-1蛋白积累密切相关，因为MEK/ERK抑制和ERK 1/2沉默均降低SIRT-1。Sirtinol对SirT-1的抑制逆转了维生素D的抗氧化作用。因此，维生素D通过激活MEK/ERK/SirT-1轴，显著降低了氧化应激引起的内皮功能障碍和损伤。
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.