The role of calcium and magnesium in the development of atherosclerosis. Experimental and clinical evidence.

Based on the findings presented in this study, we propose the hypothesis that calcium could be a mediator for the development of atherosclerosis. Figure 8 shows a schematic illustration of the hypothesis. The presence of risk factors such as hypertension, hyperlipidemia, and smoking may increase the influx of calcium into vascular ECs. We have shown that reactive oxygen species, which are considered to be a risk factor for the development of atherosclerosis, actually increase [Ca++]i in vascular ECs. Increased intracellular calcium may damage the function of ECs, resulting in platelet aggregation at the damaged site. Increased intracellular calcium may also increase uptake of macromolecules in plasma such as fibrinogen and LDL, eventually forming atherosclerotic plaque. We have also shown that the influx of calcium into vascular ECs is associated with LDL transport across vascular ECs. The pretreatment by nifedipine inhibited both the increase in [Ca++]i and the increase in LDL transport, suggesting that intracellular calcium modulates LDL transport across ECs. Growth factors released from platelets may provoke migration and proliferation of medial SMCs in the aterial intima. It has been reported that migration of SMCs from arterial media to intima is enhanced by the presence of calcium, and can be inhibited by the pretreatment of calcium antagonist. As demonstrated in this study, calcium also plays an important role in the proliferation of SMCs provoked by some kinds of growth factors such as EGF. On the other hand, we found that an increased amount of dietary Mg suppressed the development of atherosclerotic lesions in the aorta of cholesterol-fed rabbits without affecting plasma total cholesterol and HDL-cholesterol concentrations. The mechanism of action might also be related to the calcium entry blocking action. The clinical and nutritional implications of these phenomena should be investigated further. The evidences presented in this study, however, would not be sufficient to fully explain the etiological role of calcium in atherogenesis. Further studies are required to elucidate the mechanism of the contribution of calcium to atherogenesis. The efficacy of calcium antagonist for the prevention of atherosclerosis in humans should also be investigated further.