Because (i). endothelial cells are important players in cardiovascular diseases and (ii). Mg deficiency promotes atherosclerosis, thrombosis and hypertension, we evaluated whether low concentrations of Mg could directly affect endothelial behavior. We found that low Mg concentrations reversibly inhibit endothelial proliferation, and this event correlates with a marked down-regulation of the levels of CDC25B. The inhibition of endothelial proliferation is due to an up-regulation of interleukin-1 (IL-1), since an antisense oligonucleotide against IL-1 could prevent the growth inhibition observed in cells exposed to low concentrations of the cation. We also report the up-regulation of Vascular Cell Adhesion Molecule-1 (VCAM) and Plasminogen Activator Inhibitor (PAI)-1 after Mg deficiency. VCAM is responsible, at least in part, of the increased adhesion of monocytoid U937 cells to the endothelial cells grown in low magnesium. In addition, endothelial migratory response is severely impaired. By cDNA array, we identified several transcripts modulated by exposure to low Mg, some of which-c-src, ezrin, CD9, cytohesin and zyxin-contribute to endothelial adhesion to substrates and migration. In conclusion, our results demonstrate a direct role of low magnesium in promoting endothelial dysfunction by generating a pro-inflammatory, pro-thrombotic and pro-atherogenic environment that could play a role in the pathogenesis cardiovascular disease.

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Magnesium deficiency in experimental animals leads to inflammation, exacerbated immune stress response and a decrease of specific immune response. It also results in a significant increase in free radical species and subsequent tissue injury. An accelerated thymus involution was observed in Mg-deficient rats in relation to enhanced apoptosis and enhanced susceptibility to oxidative stress. To examine the stress-inducing effects of low Mg status on thymocytes, cDNA arrays were used to evaluate changes in gene expression in weaning rats submitted to Mg deficiency of short duration (2 days). Several genes exhibited changes in their expression caused by Mg deficiency before any perceptible modification in cell integrity and functions. The up-regulated genes included cytochrome c oxidase, glutathione transferase, CuZn superoxide dismutase, genes associated with the stress response (HSP70 and HSP84) and a gene involved in DNA synthesis and repair (GADD45). The down-regulated genes included Na/P cotransporter 1. These findings are consistent with altered cell growth, modifications of ion fluxes and oxidative stress described during Mg deficiency. The observation of induction of genes involved in protection and repair in cells from Mg-deficient animals provides additional evidence of the role of oxidative stress in the pathobiology of this deficiency.

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