Genotoxic Effects of Magnesium Deficiency in the Cardiovascular System and their Relationships to Cardiovascular Diseases and Atherogenesis

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

Why Do Chemotherapeutic Drugs and Radiation Induce Cardiomyopathy and Cardiac Failure in Cancer Patients: Is This a Consequence of Unrecognized Hypomagnesemia and Release of Ceramides and Platelet-Activating Factor?

The following is an excerpt from the text: Almost four decades ago [13], two of us pointed out that there was a scattered number of clinical studies that were beginning to indicate that at least three of the chemotherapeutic drugs (i.e., cisplatin, vinbastine, and bleomycin) appeared to suggest that chemotherapeutic anticancer drugs may deplete the body of magnesium (Mg) [for references and review, see [1, 2, 3, 12]. Ever since we suggested the potential danger of these drugs to the heart and cardiovascular system[13], a growing body of evidence has borne-out these initial dangers to cancer patients [e.g., for reviews see [4-11]. It appears from recent studies that cancer patients receiving cardiac transplants, who had taken chemotherapeutic drugs and/or radiation often showed unexplained, worsened depletion of Mg [for recent review, see [12]. How and why could depletion of body Mg stores, and Mg depletion from the heart and blood vessels, cause cardiac arrhythmias, elevated arterial blood pressure, prolonged QT intervals, coronary arterial vasospasm, myocardial ischemic events, myocardial infarctions, and sudden-cardiac death (SCD)

Insights into the Possible Mechanisms By Which Platelet-Activating Factor and PAF-receptors Function in Vascular Smooth Muscle in Magnesium Deficiency and Vascular Remodeling: Possible Links to Atherogenesis, Hypertension and Cardiac Failure

Platelet-activating factor (PAF) is a phospholipid mediator and cell signaling molecule which displays multiple biological and pathophysiological attributes, running the gamut from inflammation to cell differentiation and proliferation [1-4]. As is well-known, PAF interacts with specific membrane PAF-receptors (PAF-Rs) to initiate all cellular responses via specific G-proteincoupled receptors [1-4]. Although these initiated membrane receptor phenomena are mostly established for several tissuecell systems [1-8], exactly how PAF and PAF-Rs cause vascular remodeling in hypertension and atherosclerosis is not clear. A little more than 15 years ago, PAF was identified as a molecule that stimulated activation of nuclear factor-kappaB (NF-kB

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

Epidemiologic studies in North America and Europe have shown that people consuming Western-type diets are low in magnesium (Mg) content (i.e., \u3c 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

Sudden Cardiac Death in Infants, Children and Young Adults: Possible Roles of Dietary Magnesium Intake and Generation of Platelet-Activating Factor in Coronary Arteries

Magnesium (Mg) is a co-factor for more than 500 enzymes, and is the second most abundant intracellular cation after potassium. It is vital in numerous physiological, cellular and biochemical functions and systems necessary for life. Approximately 35 years ago, our laboratory suggested that a progressive, dietary deficiency and/or metabolic induced loss of Mg from the body, beginning early in life, particularly during development of the coronary arteries, could lead to coronary arterial vasospasm, ischemic heart disease, and sudden-cardiac death (SCD). Herein, we review evidence for a brand-new, novel hypothesis which combines knowledge suggesting a combined role for hypomagnesemia and platelet-activating factor (PAF) which may provide insights into unexplained SCD in infants, children, and young adults. This review documents what takes place in the cardiovascular system when the body and its tissues are subjected to lower than normal dietary Mg intake, and also provides new evidence for a series of heretofore unknown actions of PAF that are most likely involved and/or trigger coronary arterial vasospasm in the presence of low concentrations of ionized Mg levels. The roles of vascular remodeling, NF-κB and proto-oncogenes are considered to play major roles in this hypothesis

Magnesium Deficiency Results in Oxidation and Fragmentation of DNA, Down Regulation of Telomerase Activity, and Ceramide Release in Cardiovascular Tissues and Cells: Potential Relationship to Atherogenesis, Cardiovascular Diseases and Aging

The authors discuss the potential relationship between magnesium, cardiovascular diseases, and aging

Euphoria from Drinking Alcoholic Beverages May Be Due to Reversible Constriction of Cerebral Blood Vessels: Potential Roles of Unrecognized Ionized Hypomagnesemia, and Release of Ceramides and Platelet-Activating Factor

The authors discuss the feeling of euphoria when drinking alcohol. They summarize studies that suggest this feeling is due to blood vessel constriction, and explain why they believe that the specific mechanism that results in euphoria is the rapid, reversible release o free magnesium ions ([Mg2+]) coupled to the release of ceramides and platelet-activating factor (PAF)

Is the High Frequency of Postoperative Atrial Fibrillation after Cardiac and Lung Surgeries Related to Hypomagnesemia and Releases of Ceramides and Platelet-Activating Factor?

The authors discuss the possible role of hypomagnesemia, ceramides and platelet-activating factor in the incidence of postoperative atrial fibrillation after cardiac and lung surgeries

Why is Postoperative Atrial Fibrillation Difficult to Prevent and Treat: Potential Roles of Unrecognized Magnesium Deficiency and Release of Ceramide and Platelet-Activating Factor

Heart failure is a major cause of morbidity and mortality whose costs impose staggering health-care costs and often lengthy hospitalizations. Post-operative atrial fibrillation (POAF) represents a leading cause for heart failure, particularly after cardiac and lung surgeries. Although PAOF is a common cardiac arrhythmia, it is impossible to predict. As the worldwide population is aging, the incidence and prevalence of PAOF is growing. Identifying mechanisms for PAOF is attracting a considerable amount of research with no agreement on the mechanism(s). Our research on the heart and cardiovascular system, over the past 50-plus years, leads us to believe that major causes of PAOF may be an underlying magnesium deficiency (MgD) coupled to a generation/release of ceramides and platelet-activating factor (PAF). Herein, we review reasons behind our hypothesis and suggestions for testing its validity

The Expression of Platelet-Activating Factor Is Induced by Low Extracellular Mg2+ in Aortic, Cerebral and Neonatal Coronary Vascular Smooth Muscle; Cross Talk with Ceramide Production, NF–kB and Proto-Oncogenes: Possible Links to Atherogenesis and Sudden Cardiac Death in Children and Infants, and Aging: Hypothesis, Review and Viewpoint

An attempt is made, herein, to reconcile, and integrate, various phenomena associated with magnesium deficiency (MgD) in cardiovascular health, disease, and aging as well as reasons for the high incidence of sudden cardiac death in infants and young adults. With new experiments, we demonstrate, for the first time, that very low concentrations of platelet-activating factor (PAF), when added to primary cultured cerebral, neonatal coronary, and aortic vascular smooth muscle (VSM) cells (from three different mammals) promote rapid rises in free intracellular Ca2+ ions and a significant, concomitant reduction in free intracellular Mg2+ ions; these actions of PAF being curtailed with a specific membrane-receptor inhibitor of PAF. Our new experiments also demonstrate that addition of PAF to the VSM cells result in activation of NF-kB, activation of the proto-oncogenes c-fos and c-jun, a generation/release of ceramide, and synthesis of DNA; most of these actions being inhibited by a specific membrane-receptor antagonist of PAF. In addition, we show, for the first time, formation of 4-hydroxy-2-nonenal (4-HNE) in VSM cells incubated in Mg-deficient (MgD) environments or after addition of PAF. This is important because 4-HNE is a well-known inducer of hydrogen peroxide, known to be formed in MgD VSM cells and that 4-HNE is known to induce DNA damage and fragmentation, events that we have shown previously in VSM and cardiac muscle cells exposed to low Mg environments. Lastly, our experiments demonstrate that incubation of cerebral, neonatal coronary and aortic VSM cells in low Mg2+ induces: 1. rapid formation of PAF which can be attenuated greatly with a specific membrane-receptor antagonist of PAF; and 2. rises in cellular levels of ceramide, NF-kB activation and formation of the proto-oncogenes, and synthesis of DNA, all of which could be inhibited with a specific membrane-receptor antagonist of PAF. These new findings suggest major roles for PAF (and probably PAF-like lipids) and ceramide formation in the cardiovascular manifestations of MgD, inflammation, atherogenesis, aging, and sudden cardiac death in children. The significance of our new findings are reviewed in light of other works on MgD, inflammation, atherogenesis, sudden cardiac death, and aging