Search

Vasculitis is characterized as an inflammatory disease of the body’s small blood vessels, particularly in the lungs and kidneys [1-4]. Many other organ regions are usually affected which often induces morbidity and mortality [1-4].

Post-operative atrial fibrillation (POAF) is the most prevalent complication after cardiac or lung surgery, occurring in about 20-50 percent of these patients [1-5]. This event often leads to increased morbidity, thromboembolisms, strokes and long-term mortality resulting in recurring hospitalizations and increased costs. Often the cause(s) of POAF is not known. Age, previous history of atrial fibrillation (AF), hypertension, diabetes, myocardial infarction, valvular heart disease, left ventricular hypertrophy, obesity, excessive drinking of alcohol and excessive smoking present great risk factors for development of POAF [15]. According to a number of reports, the incidence of cerebral infarction and heart failure can increase two-four fold after PAOF [1-5]. Added to this, are a number of growing autopsy studies which demonstrate that many of the PAOF patients, who have died, have considerable atherosclerotic plaques on the walls of the coronary vessels leading to the idea that inflammatory events probably play an important role in the PAOF syndrome [5]. POAF is usually managed by digoxin, calcium channel blockers, betablockers, quinidine, amiodarone, direct current cardioversion, catheter ablation inside the heart, or appropriate rate control techniques to restore rhythm to normal [1-5]. Although digoxin is often utilized, it can present direct risks for POAF patients and has been associated with increased hospitalizations and mortalities [6, 7]. Such data has raised serious concerns about use of digoxin, one of our oldest and most controversial drugs . Ever since 1935 [8], digoxin and cardiac glycosides have been known to deplete the human body and heart of magnesium (Mg) [for review, see [9]]. Several studies have suggested that use of intravenous magnesium sulfate may be better than either betablockers, calcium channel blockers, or amiodarone [1, 5, 10-12]. This concept is currently under investigation by several groups in the USA and Europe. Abstract

Sphingolipids have a variety of important signaling roles in mammalian cells. We tested the hypothesis that certain sphingolipids and neutral sphingomyelinase (N-SMase) can regulate intracellular free magnesium ions ([Mg2+]i) in vascular smooth muscle (VSM) cells. Herein, we show that several sphingolipids, including C2-ceramide, C8-ceramide, C16-ceramide, and sphingosine, as well as N-SMase, have potent and direct effects on content and mobilization of [Mg2+]i in primary cultured rat aortic smooth muscle cells. All of these sphingolipid molecules increase, rapidly, [Mg2+]i in these vascular cells in a concentration-dependent manner. The increments of [Mg2+]i, induced by these agents, are derived from influx of extracellular Mg2+ and are extracellular Ca2+ concentration-dependent. Phospholipase C and Ca2+/calmodulin/Ca2+-ATPase activity appear to be important in the sphingolipid-induced rises of [Mg2+]i. Activation of certain PKC isozymes may also be required for sphingolipid-induced rises in [Mg2+]i. These novel results suggest that sphingolipids may be homeostatic regulators of extracellular Mg2+ concentration influx (and transport) and [Mg2+]i content in vascular muscle cells.

The present study tested the hypotheses that 1) short-term dietary deficiency of magnesium (21 days) in rats would result in the upregulation of sphingomyelin synthase (SMS) and p53 in cardiac and vascular (aortic) smooth muscles, 2) low levels of Mg2+added to drinking water would either prevent or greatly reduce the upregulation of both SMS and p53, 3) exposure of primary cultured vascular smooth muscle cells (VSMCs) to low extracellular Mg2+concentration ([Mg2]o) would lead to the de novo synthesis of ceramide, 4) inhibition of either SMS or p53 in primary culture VSMCs exposed to low [Mg2+]owould lead to reductions in the levels of de novo ceramide synthesis, and 5) inhibition of sphingomyelin palmitoyl-CoA transferase (SPT) or ceramide synthase (CS) in primary cultured VSMCs exposed to low [Mg2+]owould lead to a reduction in the levels of de novo ceramide synthesis. The data indicated that short-term magnesium deficiency (10% normal dietary intake) resulted in the upregulation of SMS and p53 in both ventricular and aortic smooth muscles; even very low levels of water-borne Mg2+(e.g., 15 mg·l−1·day−1) either prevented or ameliorated the upregulation in SMS and p53. Our experiments also showed that VSMCs exposed to low [Mg2+]oresulted in the de novo synthesis of ceramide; the lower the [Mg2+]o, the greater the synthesis of ceramide. In addition, the data indicated that inhibition of either SMS, p53, SPT, or CS in VSMCs exposed to low [Mg2+]oresulted in marked reductions in the de novo synthesis of ceramide.

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 Mg2+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 (Ca2+), 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 Mg2+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 Mg2+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.

Epidemiologic studies in North America and Europe have shown that people consuming Western-type diets are low in magnesium (Mg) content (i.e., < 30 - 65% of the RDA for Mg); most such diets in the USA show that 60 - 80% of Americans are consuming only 185 - 235 mg/day of Mg. Low Mg content in areas of soft-water, and Mg-poor soil, is associated with high incidences of ischemic heart disease (IHD), coronary artery disease, hypertension, and sudden cardiac death (SCD). It is clear that the leading underlying cause of death worldwide is atherosclerosis. Importantly, both animal and human studies have shown an inverse relationship between dietary intake of Mg and atherosclerosis. The myocardial level of Mg has consistently been observed to be lower in subjects dying from IHD and SCD in soft-water areas than those in hard-water areas. Over the past 20 years, our laboratories, using several types of primary cultured vascular smooth muscle (VSM) cells, and myocardial cells, demonstrated that declining levels of extracellular Mg ([Mg2+]0) activated several enzymatic pathways to produce increases in cellular sphingolipids, particularly ceramides which are known to exert numerous types of cardiovascular manifestations including inflammatory effects ; the latter play important roles in atherogenesis and cardiovascular diseases. Approximately 20 years ago, we reported that low [Mg2+]0 caused formation of platelet-activating factor (PAF) as well as other types of PAF-like molecules and suggested that these molecules might be causative agents in low Mg2+- induced IHD and SCD. Herein, we review results and data from our labs which strongly support roles for ceramides, PAF and PAF-like lipids in low [Mg2+]0-induced IHD and SCD.

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.

Numerous recent,epidemiological studies reveal that Western populations are growing more and more deficient in daily Mg intake which have been linked to etiology of cardiovascular (CV) diseases. A growing body of evidence suggests that a major missing link to this dilemma may reside within the sphingolipid-ceramide pathways. For the past 25 years , our labs have been focusing on these pathways in Mg-deficient mammals. The objective of this paper is two-fold: 1) to test various hypotheses and 2) to review the current status of the field and how protein kinase C isoforms may be pivotal to solving some of the CV attributes of Mg deficiency. Below, we test the hypotheses that: 1) short-term dietary deficiency of magnesium (MgD) would result in the upregulation of protein kinase C (PKC) isoforms in left ventricular (LV) and aortic smooth muscle (ASM) and serum; 2) MgD would result in a release of select cytokines and an upregulation of NF-kB in LV and ASM, and in primary cultured aortic smooth muscle cells (PCASMC); 3) MgD would result in an activation of the sphingolipid salvage pathway in LV and ASM, and in PCASMC; 4) MgD would result in a synthesis of sphingosine, but not sphinganine, in PCASMC which could be inhibited by fumonisin B1 (FB) an inhibitor of ceramide synthase (CS), but not scyphostatin an inhibitor of neutral sphingomyelinase (N-SMase); 5) incubation of PCASMC (in low Mg(2+)) with the PKC-mimic PMA would result in release and synthesis of NF-kB, cytokines, and ceramide but not sphingosine. The new data indicate that short-term MgD (10% normal dietary intake) result in an upregulation of all three classes of PKC isoforms in LV, aortic muscle and in serum coupled to the upregulation of ceramide, NF-kB activation, and cytokines. High degrees of linear correlation were found to exist between upregulation of PKC isoforms, p65 and cytokine release, suggesting cross-talk between these molecules and molecular pathways. Our experiments with PCASMCs demonstrated that MgD caused a pronounced synthesis of sphingosine (but not sphinganine), which could be inhibited with fumonisin B1, but not by scyphostatin; use of PMA stimulation released ceramide but not sphingosine suggesting a role for the "sphingolipid salvage pathway" in MgD vascular muscle. Use of different PKC pharmacological inhibitors suggested that although all three classes of PKC molecules, i.e., classical, novel, and atypical, play roles in MgD-induced synthesis/release of ceramide, sphingosine, and cytokines as well as activation of NF-kB, to varying degrees, PKC-zeta appears to play a greater role in these events than any of the other PKC isoforms; a specific PKC-zeta inhibitory peptide inhibited formation of sphingosine. Even low levels of water-borne Mg (e.g., 15 mg/l/day) either prevented or ameliorated the upregulation of all three classes of PKC isoforms. An attempt is made to integrate our new data with previous information in order to possibly explain many of the cardiovascular effects of MgD.

The present study tested the hypotheses that 1) short-term (ST) dietary deficiency of magnesium (MgD; 21 days) in rats would result in the upregulation of neutral-, acid-, and alkaline- sphingomyelinases SMases) in cardiac and vascular smooth muscles (VSMCs), 2) ST MgD would result in an upregulation of proto-oncogenes, i.e., c-Fos and c-Jun, as well as the p65 and c-Rel components of NF-κB in cardiac and VSMCs, 3) low levels of Mg(2+) added to drinking water would either prevent or greatly reduce the upregulation of the SMases and proto-oncogene expression, 4) exposure of primary cultured VSMCs to low extracellular Mg(2+) concentration would lead to release of ceramide in both cerebral and aortic VSMCs, 5) specific inhibitors of neutral- and acid-SMAs would reduce the release of ceramide in cultured VSMCs exposed to low extracellular Mg(2+), and 6) specific inhibitors of neutral- and acid-SMases would lead to reductions in the expression of c-fos, c-Jun, and NF-κB components. The data indicate that neutral-, acid-and alkaline-SMases exist in rat cardiac and VSMCs. ST MgD resulted in over 150% increases in SMase activity and proto-oncogene expression in left and right ventricular muscle, atrial muscle, and abdominal aortic smooth muscle; even very low levels of Mg(2+) added to drinking water either prevented or ameliorated the activation of all 3-SMases as well as expression of c-Fos and c-Jun; scyphostatin and desipramine reduced the low Mg(2+) - induced expression of the proto-oncogenes as well as p65 and c-Rel in VSMCs. Exposure of the VSMCs to low Mg(2+) resulted in more than a 100% increase in release of ceramide; scyphostatin and desipramine reduced greatly the release of ceramide from the VSMCs. We believe when the present data are viewed in light of our previous, recent findings on the effects of Mg deficiency on most of the major enzymes in the sphingomyelin-ceramide pathway, that they could provide a rational basis for the treatment and prevention of drug-resistant hypertension, atherogenesis, and difficult-to-treat forms of cardiac failure.

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.