Magnesium: Forgotten Mineral in Cardiovascular Biology and Atherogenesis

Abstract

In this review, a rationale is presented for how hypercholesterolemia, hypertension, diabetes mellitus (DM), end-stage renal disease (ESRD), prolonged stress, and exposure to magnesium (Mg)-wasting drugs can lead to atherosclerosis, ischemic heart disease, and stroke. The data, accumulated so far, indicate that Mg defi ciency caused either by a poor diet or errors in Mg metabolism may be a missing link between diverse cardiovascular risk factors and atherogenesis. Early data from our laboratory and others indicate that reduction in extracellular free Mg ions can induce an entire array of pathophysiological phenomena known to be important in atherogenesis, that is, vasospasm, hypoxia, increased vascular reactivity, and elevation in intracellular calcium (Ca). More recent data has demonstrated molecular events, pointing the way to atherogenesis: that is, formation of pro-infl ammatory agents, generation of free radicals, platelet aggregation, modulation of macrophage and leukocyte mobility, and emigration across the endothelial wall. Finally, oxidation of lipoproteins, changes in membrane fatty acid saturation, changes in membrane plasmalogens, and N-phospholipids suggest alterations in intracellular lipid signals. It has been shown that Mg defi ciency can modulate membrane sphingomyelinase, generate vasoactive and pathogenic sphingolipids, which could alter multiple intracellular signaling pathways, modulate transcription factors, and thus cause intimal plaque formation.Hypercholesterolemia, hypertension, DM, immune injury, ESRD, renal dialysis, prolonged stress, obesity, and smoking are widely accepted as risk factors for atherosclerosis. No common link has been identifi ed that forms a rational basis to these disorders and atherogenesis. Moreover, it is not clear how lipoproteins, Ca 2+ , and macrophages gain access to the normally impermeable arterial walls or what allows plyable, physiological vascular smooth muscle (VSM) cells to change their state (phenotype) from a contractile to a noncontractile, synthetic cell, 1,2 and how these diverse risk factors lead to ischemic heart disease (IHD) and stroke.Until relatively recently, it was not believed that Mg, a common essential dietary element and electrolyte, played any role in maintaining normal cardiovascular dynamics. This lack of understanding is most likely a refl ection 239

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

“…Most such diets in the U.S.A. show that 60 -80% of Americans are consuming only 185-235 mg Mg/day [4][5][6]. Low Mg content in drinking water found in areas of soft water and Mg-poor soil, is associated with high incidences of ischemic heart disease, severe atherosclerosis, coronary vasospasm, hypertension, hyperlipidemia, diabetes, and sudden cardiac death [4,[7][8][9][10][11][12][13][14]. Both animal and human studies have shown an inverse relationship between dietary intake of Mg and atherosclerosis [4,13,[15][16][17][18][19].…”

“…Low Mg content in drinking water found in areas of soft water and Mg-poor soil, is associated with high incidences of ischemic heart disease, severe atherosclerosis, coronary vasospasm, hypertension, hyperlipidemia, diabetes, and sudden cardiac death [4,[7][8][9][10][11][12][13][14]. Both animal and human studies have shown an inverse relationship between dietary intake of Mg and atherosclerosis [4,13,[15][16][17][18][19]. The myocardial level of Mg has consistently been observed to be lower in subjects dying from ischemic heart disease and sudden cardiac death in soft water areas [4,7,9,11,20,21].…”

“…Both animal and human studies have shown an inverse relationship between dietary intake of Mg and atherosclerosis [4,13,[15][16][17][18][19]. The myocardial level of Mg has consistently been observed to be lower in subjects dying from ischemic heart disease and sudden cardiac death in soft water areas [4,7,9,11,20,21]. Mg plays an essential role in more than 500 enzymatic reactions and is required for all energy-generating reactions and oxidative phosphorylation.…”

“…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].…”

“…Using sensitive, specific Mg 2+ -ion-selective electrodes, it has been shown that patients with hypertension, ischemic heart disease, cardiac failure, strokes, diabetes (types 1 and 2), gestational diabetes, renal disease-induced vascular changes (i.e., atherosclerosis and inflammation) exhibit significant depletion of serum/plasma and tissue levels of ionized, but not total, Mg [4,16,17,[26][27][28][29][30][31][32][33][34][35]. Moreover, dietary deficiency of Mg, under very-controlled laboratory conditions, in rats and rabbits has been shown to cause vascular remodeling concomitant with hypertension and atherogenesis (i.e., arteriolar wall hypertrophy and alterations in arterial wall matrices) of unknown origin [4,6,[15][16][17][36][37][38][39].…”