Short-term magnesium deficiency results in decreased levels of serum sphingomyelin, lipid peroxidation, and apoptosis in cardiovascular tissues

Abstract

The present study tested the hypothesis that short-term dietary deficiency of magnesium (Mg) (21 days) in rats would 1) result in decreased serum(s) [the present study tested the levels of Mg, sphingomyelin (SM), and phosphatidylcholine (PC)]; 2) promote DNA fragmentation, lipid peroxidation (LP), and activation of caspase-3 in cardiac (ventricular and atrial) and vascular(aortic) muscle; and 3) low levels of Mg(2+) added to drinking water would either prevent or greatly ameliorate these manifestations. The data indicate that short-term Mg deficiency (10% normal dietary intake) resulted in profound reductions in serum-ionized Mg and total Mg with an elevation in serum-ionized calcium (Ca(2+)), significant lowering of serum SM and serum PC, with concomitant LP, DNA fragmentation, and activation of caspase-3 in ventricular (right and left chambers), atrial (right and left chambers) and abdominal aortic smooth muscle. The greater the reduction in serum-ionized Mg, the greater the effects on DNA fragmentation, LP, and caspase-3 activity. The intake of water-borne Mg(2+) at all levels greatly attenuated or inhibited the reductions in serum SM and serum PC, activation of LP, DNA fragmentation, and the activation of caspase-3; even very low levels of Mg(2+) in drinking water (i.e., 15 parts.million(-1).day(-1)) were cardio- and vascular protective. In addition, we demonstrate that short-term dietary deficiency of Mg probably results in a downregulation of SM synthase and a decreased synthesis of PC.

Regulated RIPK3 Necroptosis is Produced in Cardiovascular Tissues and Cells in Dietary Magnesium Deficiency: Roles of Cytokines and Their Potential Importance in Inflammation and Atherogenesis

“…Our results, also encourages the idea that, water intake (e.g., from tap waters, well waters, bottled waters, beverages using tap/well/spring waters, or desalinated waters) should contain at least 25-40 mg/liter/day of Mg 2+ [58][59][60]76,77,81]. In this context, our group has performed several conclusive experiments and highlighted most of the detrimental pathophysiological implications of Mg deficiency, which includes decreased cardiac output, decreased myocardial contractility, decreased coronary blood flows, mitochondrial release of cytochrome C, lipid peroxidation of cardiac and vascular muscle membranes, increased cellular levels of NO and p53, release of cytokines and chemokines, increased cellular entry of calcium ions and overload, increases in membrane permeability, myocardial acidification, loss of cellular ATP, DNA damage, shortening of telomeres, apoptosis, and necroptosis [11,41,42,57-61,72-79-83].…”

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].…”

“…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.…”

“…Mg plays an essential role in more than 500 enzymatic reactions and is required for all energy-generating reactions and oxidative phosphorylation. Mg is a natural calcium (Ca) channel blocker on myocardial and vascular smooth muscle cells [4,16,17,22,23], which was first demonstrated by The Alturas [22,23], and is a natural statin in that it lowers blood cholesterol, LDL, and triglycerides, and lowers arterial blood pressure [4][5][6][15][16][17][18]24,25].…”

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

“…Such paradigms, using variations in Mg 2ϩ , also cause membrane oxidation, truncation of membrane fatty acids, and the activation of apoptotic pathways (i.e., caspase-3, apoptotic protease activation factor-1, and release of mitochondrial cytochrome c) concomitant with the significant activation of neutral sphingomyelinase (N-SMase) and alterations in membrane sphingomyelin (SM), leading to the release of ceramides in cultured VSMCs (14 -16, 68). Very recently, using a short-term (21 days) rat model of dietary MgD, we noted decreased levels of serum SM, lipid peroxidation, and fragmentation of DNA coupled with generation of the tumor suppressor-transcription factor p53 in the left ventricular (LV) and right ventricular (RV) muscles as well as in atrial muscle and vascular smooth muscle (14,16). These alterations (including the change in serum SM) were highly correlated (P Ͻ 0.01) with the levels of serum ionized Mg levels (14,16,68).…”