Magnesium deficiency upregulates serine palmitoyl transferase (SPT 1 and SPT 2) in cardiovascular tissues: relationship to serum ionized Mg and cytochromec

Abstract

The present work tested the hypothesis that a short-term dietary deficiency of magnesium (Mg) (21 days) in rats would result in the upregulation of the two major subunits of serine palmitoyl-CoA-transferase, serine palmitoyl transferase (SPT 1) and SPT 2 (the rate-limiting enzymes responsible for the de novo biosynthesis of ceramides) in left ventricular, right ventricular, and atrial heart muscle and abdominal aortic smooth muscle, as well as induce a reduction in serum sphingomyelin concomitant with the release of mitochondrial cytochrome c (Cyto c) in these tissues. Our data indicate that short-term Mg deficiency (MgD) resulted in an upregulation of SPT 1 and SPT 2, concomitant with a very significant release of Cyto c in left ventricular, right ventricular, atrial, and abdominal aortic smooth muscle. Short-term MgD also produced a lowering of serum sphingomyelin and ionized Mg. The greater the reduction in serum ionized Mg, the greater the upregulation of SPT 1 and 2 and the more the increase in free Cyto c. The data suggest that MgD, most likely, causes a biosynthesis of ceramides via two pathways in cardiovascular tissues, viz., via the activation of serine palmitoyl-CoA-transferase and sphingomyelinase, which lead to apoptotic events via intrinsic (present study) and extrinsic pathways (previous studies). Low levels of drinking water Mg were cardio- and vasculoprotective.

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

“…We also noted that MgD diets resulted in fragmentation of DNA [24], a release of cytochrome C [65], an increased expression of apoptotic protease factor-1 [65], and an activation of caspase-3 (needed for apoptosis) [24], hallmarks of atherogenesis [42]. When specific inhibitors of SMase and SPT (1 and 2) were utilized, in primary cell cultures of VSM cells, exposed to low Mg 2+ environments, we noted an inhibition of formation and release of ceramides, inhibition of DNA fragmentation, inhibition of release of mitochondrial cytochrome C, reduced expression of apoptotic protease factor-1, and inhibition of activation of caspase-3 [65]. We believe, collectively, these new studies lend support to our hypothesis that generation and release of ceramides are pivotal molecules in the initiation of cellular and molecular events leading to inflammatory events and atherogenesis, at least in MgD states.…”

“…Recently, we have reported that magnesium deficient diets given to rats for only 21 days results in an upregulation of SMase, SPT-1, and SPT-2 in a variety of cardiovascular tissues and cells as well as decreased levels of SM and phosphatidylcholine (PC) [65]. We also noted that MgD diets resulted in fragmentation of DNA [24], a release of cytochrome C [65], an increased expression of apoptotic protease factor-1 [65], and an activation of caspase-3 (needed for apoptosis) [24], hallmarks of atherogenesis [42].…”

“…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.…”

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

“…Previously, we have shown that the production of low- [Mg 2ϩ ] o environments, either in vivo (e.g., identical model of MgD used here; Refs. 15, 16) or in primary cultured vascular cells (15,55), results in the activation of SMase, SMS, and SPT (SPT-1 and SPT-2) and the production of ceramides. Thus the present findings, when taken together with the latter studies, indicate that ceramide is most likely generated in cardiovascular tissues and cells in low [Mg 2ϩ ] o by four major enzymes in the sphingolipid pathway.…”

“…No direct information exists, however, on the potential latter pathway of activation by low [Mg 2ϩ ] o in cardiovascular tissues and/or cells. However, using primary cerebral and peripheral VSMCs in culture, exposed to low[Mg] o , we have found that a specific (and selective) inhibitor of CS, namely fumonisin B1, resulted in a marked reduction in de novo synthesis of ceramide (15), presumably suggestive of an upregulation of CS. Whether a dietary deficiency of Mg results in upregulation of CS is not known.…”