Short-term magnesium deficiency upregulates ceramide synthase in cardiovascular tissues and cells: cross-talk among cytokines, Mg²⁺, NF-κB, and de novo ceramide

Abstract

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, ...

Potential Roles of Magnesium Deficiency in Inflammation and Atherogenesis: Importance and Cross-talk of Platelet-Activating Factor and Ceramide

“…These factors will sustain and perpetuate the atherogenic process forming, eventually, fibrous tissue and further enlargement of the lesion, which will overlie a core of lipid resulting in plaques and necrotic tissue. Using rabbits and rats, we have demonstrated that feeding the animals diets low in Mg (similar to the levels found in American diets) results in all of the hallmarks of atherosclerosis, i.e., inflammation followed by release of hydrolytic enzymes, release of cytokines, release of chemokines and growth factors involved in the early stages of the atherogenic process demonstrating lesions and plaques on the inner surfaces of the endothelial walls followed by invasion of VSM cells which become transformed phenotypes [4,16,17,43,45].…”

“…It has been shown by our group [4,25,43,51] and others [52][53][54] that ceramides, in increased levels, found in the atherogenic process[mixed in plaques; unpublished findings ], at least in rabbits, and stimulated in MgD states could be important causal and initiating agents [16,17].…”

“…At every stage of this process, macrophages, monocytes, and T-lymphocytes are attracted to the endothelium lining the blood vessel walls [41,42]. Activation of these cells then would be expected to result in release of hydrolytic enzymes, cytokines, and growth factors, which have been shown to be released in states of magnesium deficiency [43][44][45]. These factors will sustain and perpetuate the atherogenic process forming, eventually, fibrous tissue and further enlargement of the lesion, which will overlie a core of lipid resulting in plaques and necrotic tissue.…”

“…Since we have demonstrated in both rats and rabbits fed low Mg diets that increased levels of both ceramides and PAF are found, in situ , in all chambers of the heart , aortae and coronary blood vessels, and these manifestations were associated with increased plaques, elevated serum cholesterol , elevated trigycerides , elevated ceramides, and increased generation of PAF [4,[15][16][17]24,25,43,45,51,65,69,81], it is highly unlikely that these in-vivo manifestations are merely epiphenomena. However, in order to solidify our hypothesis, regarding inflammation and atherogenesis (induced by low dietary Mg), one could utilize PAF knock-out or knock-down rats and mice subjected to low dietary Mg.…”

“…The normal mediators for these processes to take place are: adhesion molecules; cytokines; and chemokines. Interestingly, all of these same mediators are needed for atherogenesis [40][41][42], and have been demonstrated recently to be formed, rapidly, in magnesium-deficient states [43][44][45].…”