Magnesium deficiency promotes a pro-atherogenic phenotype in cultured human endothelial cells via activation of NFkB

Abstract

Phenotypic modulation of endothelium to a dysfunctional state contributes to the pathogenesis of atherosclerosis, partly through the activation of the transcription factor NFkB. Several data indicate that magnesium deficiency caused by prolonged insufficient intake and/or defects in its homeostasis may be a missing link between diverse cardiovascular risk factors and atherosclerosis. Here we report that endothelial cells cultured in low magnesium rapidly activate NFkB, an event which is prevented by exposure to the anti-oxidant trolox. It is well known that NFkB activation correlates with marked alterations of the cytokine network. In the present study, we show that exposure of endothelial cells to low magnesium increases the secretion of RANTES, interleukin 8 and platelet derived growth factor BB, all important players in atherogenesis. Moreover, we describe the increased secretion of matrix metalloprotease-2 and -9 and of their inhibitor TIMP-2. Interestingly, by zymography we show that metalloprotease activity predominated over the inhibitory effect of TIMP-2. These results indicate that low magnesium promotes endothelial dysfunction by inducing pro-inflammatory and pro-atherogenic events.

Magnesium in Man: Implications for Health and Disease

“…In contrast, high Mg 2ϩ in the cell increases eNOS activity and suppresses the synthesis of vasoconstrictor endothelin-1 (277,327). In conditions of low Mg 2ϩ -induced oxidative stress, the endothelium develops a state of permanent inflammation, which is marked by increased NFB activitiy (153). NFB is the master regulator of transcription of cytokines and pro-inflammatorty genes, including IL-1␣.…”

“…As a result of this local inflammation, the vessel wall will recruit monocytes and trigger the proliferation and migration of vascular smooth muscle cells. These processes are facilitated by the increased expression of matrix metalloproteases 2 and 9 in low Mg 2ϩ conditions (153,382). Eventually low Mg 2ϩ concentrations may, therefore, result in atherosclerosis, vascular calcifications, or thrombosis.…”

Oral magnesium supplementation improves endothelial function and attenuates subclinical atherosclerosis in thiazide-treated hypertensive women

“…Hypomagnesemia has been implicated in the pathogenesis of high blood pressure (BP), endothelial dysfunction, dyslipidemia and inflammation [21][22][23], with these factors being associated with arterial stiffness [24,25].…”

Mg status in inflammation, insulin resistance, and associated conditions

“…Ferrè et al [62] in experimental testing in vitro with human umbilical vein endothelial cells (HUVEC) evaluated the effects of 24 h Mg restriction on the path of NFkB by electrophoretic mobility shift assay (EMSA) and used proteomic analysis to investigate proteins involved in inflammation and atherogenesis. Their results showed major proteins in atherogenesis as RANTES, IL-8, PDGF-BB, TIMP-2, and GM-CSF, as well as activation of the NFkB in the culture medium with low concentration of Mg (0.1 mM).…”