Low magnesium promotes endothelial cell dysfunction: implications for atherosclerosis, inflammation and thrombosis.
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.
Maier
Jeanette A M
JA
Department of Preclinical Sciences LITA Vialba, University of Milan, Via GB Grassi 74, 20157, Milan, Italy. jeanette.maier@unimi.it
Malpuech-Brugère
Corinne
C
Zimowska
Wioletta
W
Rayssiguier
Yves
Y
Mazur
Andrzej
A
D001161:Arteriosclerosis / Q000473:pathology*; D002448:Cell Adhesion / Q000187:drug effects; D018797:Cell Cycle Proteins / Q000378:metabolism; D002455:Cell Division / Q000187:drug effects; D002460:Cell Line; D002465:Cell Movement / Q000187:drug effects; D042783:Endothelial Cells / Q000187:drug effects* / Q000473:pathology*; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D007249:Inflammation / Q000473:pathology; D007375:Interleukin-1 / Q000096:biosynthesis; D008274:Magnesium / Q000494:pharmacology*; D008275:Magnesium Deficiency / Q000473:pathology*; D017395:Plasminogen Activator Inhibitor 1 / Q000096:biosynthesis; D016392:Proto-Oncogene Proteins pp60(c-src) / Q000378:metabolism; D013927:Thrombosis / Q000473:pathology*; D020687:cdc25 Phosphatases / Q000378:metabolism
D018797:Cell Cycle Proteins; D007375:Interleukin-1; D017395:Plasminogen Activator Inhibitor 1; D016392:Proto-Oncogene Proteins pp60(c-src); C517008:CDC25B protein, human; D020687:cdc25 Phosphatases; D008274:Magnesium