BT. Short-term magnesium deficiency upregulates ceramide synthase in cardiovascular tissues and cells: crosstalk among cytokines, Mg 2ϩ , NF-B, and de novo ceramide. Am J Physiol Heart Circ Physiol 302: H319 -H332, 2012. First published October 7, 2011 doi:10.1152/ajpheart.00453.2011.-The present study tested the hypotheses that 1) short-term dietary deficiency (MgD) of magnesium (21 days) would result in the upregulation of ceramide synthase (CS) in left ventricular (LV), right ventricular, atrial, and aortic smooth muscle, as well as induce a synthesis/release of select cytokines and chemokines into the LV and aortic smooth muscle and serum; 2) exposure of primary cultured vascular smooth muscle cells (VSMCs) to low extracellular Mg concentration would lead to the synthesis/release of select cytokines/chemokines, activation of N-SMase, and the de novo synthesis of ceramide; and 3) inhibition of CS by fumonisin B1 (FB1) or inhibition of neutral sphingomyelinase (N-SMase) by scyphostatin (SCY) in VSMCs exposed to low Mg would result in reductions in the levels of the cytokines/chemokines and lowered levels of ceramide concomitant with inhibition of NF-B activation. The data indicated that shortterm MgD (10% normal dietary intake) resulted in the upregulation of CS in ventricular, atrial, and aortic smooth muscles coupled to the synthesis/release of 12 different cytokines/chemokines, as well as activation of NF-B in the LV and aortic smooth muscle and sera; even very low levels of water-borne Mg (e.g., 15 mg·l Ϫ1 ·day Ϫ1 ) either prevented or ameliorated the upregulation and synthesis of the cytokines/chemokines. Our experiments also showed that VSMCs exposed to low extracellular Mg resulted in the synthesis of 5 different cytokines and chemokines concomitant with synthesis/release of ceramide. However, inhibition of the synthesis and release of ceramide by either FB1 or SCY attenuated, markedly , the generation of ceramide, release of the cytokines/chemokines, and activation of NF-B (as measured by activated p65 and cRel). cardiac muscle; vascular muscle; p65; cRel; neutral sphingomyelinase; water-borne magnesium IMPROPER NUTRITION, HIGH CHOLESTEROL intake, and fatty diets are known to promote lipid deposition and accelerate growth and transformation of smooth muscle cells (SMCs) in the vascular wall (20,40,57). Over the past five decades, an accumulation of epidemiological and experimental data have indicated that a reduction in the dietary intake of Mg, as well as low Mg content in drinking water, is a risk factor for the development of hypertension, atherosclerosis, vasospasm, sudden cardiac death, stroke, and inflammatory conditions by ill-defined mechanisms (e.g., see Refs. 1,[4][5][6][17][18][19][27][28][29]35,38,46,48,49,63,64,65,67,72). Hypermagnesemic diets have been shown to ameliorate hypertension and atherogenesis (4,5,7,8,18,23,67). At present, the average dietary intake of Mg has declined from ϳ450 -485 mg/day in 1900 to ϳ185-235 mg/ day for large segments of the North American population (4, 30, ...

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The authors present evidence for a novel, new hypothesis whereby magnesium deficiency (MgD) acts as a genotoxic agent which probably causes numerous, hertofore, unrecognized consequences, even over a short-term, on the physiological, molecular and biochemical machinery of cardiovascular tissues and cells. The end result of these genotoxic effects of MgD probably plays important roles in the etiology and generation of diverse cardiovascular diseases, atherosclerosis, inflammation, and strokes via alterations in the epigenome of cardiovascular tissues and cells. The importance of adequate water-borne and dietary levels of Mg is emphasized.

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