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

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.