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Molecular biology of atherosclerosis,
Proceedings of the 57th European Atherosclerosis Society Meeting. Edited by M.J. Halpern.c © John Libbey & Company Ltd, pp. 507-512.

Chapter 113
Magnesium and the cardiovascular system: I. New experimental data on magnesium and lipoproteins


Y. RAYSSIGUIER1, E. GUEUX1, V. DURLACH2, J. DURLACH3, F. NASSIR1 and
A. MAZUR1

1INRA Centre de Recherches Clermont-Fd/Theix 63122 France; 2CHU Reims 51092, France; 3SDRM, 64 rue de Longchamp, F-92200 Neuilly, France


Systematic intervention studies in humans that document a cause-effect relationship between Mg status and atherosclerosis have not yet been performed. With this reservation in mind, the following discussion will examine indirect evidence in experimental animals that will strongly suggest a role of magnesium in the aetiology of dyslipidaemia and atherosclerosis.

Magnesium and lipoproteins

Abundant evidence exists from studies in laboratory animals that magnesium affects lipid metabolism1,2. Experiments were conducted in rats fed a control or Mg-deficient diet3. The concentrations of chylomicrons VLDL and LDL are higher in Mg-deficient rats, but the concentration of HDL is less than in controls. Triglycerides are elevated and this is primarily due to an increase in chylomicrons and VLDL concentrations. Cholesterol levels increase in the VLDL and LDL fractions and decrease in the HDL fraction. The free cholesterol increases and esterified cholesterol decreases3. In contrast to the slight modifications in total cholesterol in severe Mg deficiency of short duration, other experiments indicate a significant increase in total cholesterol during moderate Mg deficiency of long duration2. Reflecting the high concentration of triglycerides, there is an increase in plasma apo B in the plasma of deficient rats4. The objective of a recent study was to compare plasma lipoprotein composition in rats fed a control or Mg-deficient diet5. In the Mg-deficient rats the percent composition of triglycerides is elevated and that of protein is reduced in VLDL, LDL and HDL. Whereas the proportion of cholesterol is reduced in LDL and HDL, that of phospholipid is decreased in HDL. Mg deficiency induces a decrease and a relative increase in the percentage composition of apo E and apo C for VLDL, respectively. In HDL from Mg-deficient rats, the proportion of apo A-I is higher than normal. Apo A-IV is lower than normal and apo E was virtually absent5. Furthermore, Mg deficiency affects fatty acid composition of plasma lipids. Mg deficient rats show decreased levels of stearic acid, increased levels of oleic and linoleic acids and decreased levels of arachidonic acid6. Mg deficiency decreases the activity of delta-6-desaturase, the enzyme which regulates the biosynthesis of arachidonic acid6,7,8. Plasma VLDL bulk fluidity was estimated by fluorescence polarization using the classical probe DPH. VLDL fluorescence anisotropy is decreased in Mg-deficient rats as compared to control animals (unpublished data). Thus magnesium deficiency induces modifications in physico-chemical characteristics of lipoproteins.

Lipoprotein metabolism

The accumulation of lipids in the blood occurs when their rate of entry into the blood exceeds their rate of removal. The origin of lipids could result from three mains sources: dietary lipids, adipose tissue lipids and lipids synthesized in the liver.

Dietary lipids

Increased magnesium intake increases fat excretion9. These observations suggest that orally administered Mg salts exert their lipid-lowering effects by direct interference with lipid absorption and increased excretion of faecal metabolized cholesterol, the bile acids. The effect is similar although weaker to that of cholestyramine. Although the effect of magnesium on lipid absorption is of interest, the effect is weak when compared with other treatments, and alterations in plasma lipids in magnesium deficient animals implicate other interactions between magnesium and lipid metabolism2.

Adipose tissue and stress

Mg deficiency potentiates the effect of stress since catecholamines release is increased in Mg-deficient animals1,2,10. Stress is a major contributing factor to ill health, particularly cardiovascular diseases and atherosclerosis, and there are possible connections between stress and altered lipoprotein metabolism11. Mg deficiency enhances catecholamine secretion which results in an increase in lipolysis and blood plasma magnesium has been shown to decrease when lipolysis is increased1,2. Enhancement in lipolysis and subsequent elevation of plasma free fatty acids levels may lead to an increase in hepatic VLDL-triglycerides synthesis and secretion and elevated plasma triglyceride concentration. However, the slight elevation of plasma free fatty acids levels does not appear to be a major component for hyperlipaemia in Mg-deficient animals1,2.

Liver

The increase in plasma triglycerides and cholesterol observed in Mg deficient rats may be the result of increased hepatic synthesis. An increase in the rate of liver lipogenesis is observed in Mg-deficient rats but the effect is weak compared to other nutritional conditions and HMG-CoA reductase expressed activity is decreased in Mg-deficient rats (unpublished data). The hepato-biliary pathway is the main route for removal of cholesterol from the body and a recent study was designed to examine the effect of Mg deficiency on biliary secretion. Bile flow is significantly lower in Mg-deficient rats than in controls and the cholesterol concentration in bile is decreased (unpublished data). Thus cholesterol output is markedly reduced in deficient animals. It is noteworthy that the hepatic microsomal HMG-CoA reductase activity is decreased in the same animals and that Mg deficiency is probably accompanied by low hepatic cholesterogenesis. The origin of reduced hepatic cholesterogenesis is uncertain and might be the result of an increased uptake of TG-rich lipoproteins by the liver. This might result from a decreased peripheral utilization. Apo B is synthetized in enterocytes and hepatocytes. Recent experiments from our laboratory indicate that apo B mRNA levels in the liver and intestine of Mg-deficient rats are significantly increased as compared to control rats. These results showing a stimulatory effect of Mg deficiency on apo B gene expression are of interest since secretion of VLDL is totally dependent upon apo B. Thus, one cause of hyperlipaemia may be overproduction of apo B entering the circulations. Future investigations should clarify the influence of Mg on apo B synthesis.

Lipoprotein catabolism

Other experiments indicate that decreased clearance of TG-rich lipoproteins is a major mechanism contributing to hyperlipaemia in Mg-deficient rats. By studying intralipid clearance, we were able to show that hyperlipaemia developed because triglycerides removal was impaired1,2. Moreover, Mg deficient rats exhibited delayed clearance of 14C-labelled VLDL compared to control rats whereas the catabolism of 125I-LDL was not affected. Mg deficiency does not affect the expression of LDL receptors by the liver4. The lipolytic cascade for plasma triglycerides is a complicated process and involves interactions of lipoproteins with lipoprotein lipase and hepatic triglyceride lipase. Defective lipolysis of VLDL triglycerides can theoretically result from abnormalities or deficiency in these enzymes or abnormalities in lipoproteins that render them poor substrates for lipolytic enzymes. These possibilities have been addressed in recent studies12. The results indicate that postheparin lipolytic activity (PHLA) in deficient rats is substantially lower than in control animals. Hepatic lipase is significantly decreased in Mg-deficient rats, but the low PHLA is due mainly to a decline in lipoprotein lipase activity. Moreover, the alterations in the lipoprotein profile are the results of a reduction in the availability of LPL and not of an abnormality in the lipoproteins themselves12. The decrease of LPL activity may be due to a selective decrease in the heparin releasable pool of enzyme. Other findings indicate that the decrease in the ratio of esterified cholesterol to total cholesterol in plasma from Mg-deficient animals is the result of a decreased activity of lecithin cholesterol acyl transferase13.

Membrane fluidity

The secondary effects of Mg deficit on cell constituents are well known. These include loss of potassium, accumulation of sodium and calcium. Several results support the hypothesis that defective membrane function could be the primary lesion underlying the cellular disturbances that occur in Mg deficiency14,15,16. Fluorescence polarization was used to compare the fluidity of membrane preparation from Mg-deficient and control rats. Plasma and subcellular membranes from Mg-deficient animals were more fluid than those of control rats. An increased permeability of the membrane to ions may be caused by looser packing among the molecules of the bilayer. The loss of Mg from the membrane may contribute to the increased fluidity owing to the direct binding of the phospholipid headgroups, but metabolic alterations of the lipid composition are also involved in the modification of membrane fluidity that occurs during Mg deficiency. One of the consequences of damage to the membrane in Mg-deficient animals is the inflow of relatively large amounts of calciuml6.

Lipid peroxidation

The thiobarbituric acid reacting substances used as a measure for lipid peroxidation are increased in the plasma and in the liver of Mg-deficient rats7 (and unpublished data). Moreover Mg-deficient red blood cells exhibit an enhanced sensitivity to oxidative stress when lipid oxidation was determined by MDA formations17. When the effect of Mg deficiency on polymorphonuclear leukocyte function in rats was examined, superoxide anion production was significantly increased in deficient rats18. A recent observation from our laboratory indicates that VLDL and LDL lipoprotein fractions of Mg-deficient rats as compared to control rats are more susceptible to induced oxidative damage when lipid peroxidation was induced in vitro by phenylhydrazine. Modified LDL are no longer recognized by B/E receptors but instead bind to macrophages which act as scavenger receptors leading to accumulated levels of esterified cholesterol and foam cells19. Macrophages have been implicated as the prime source of foam cells in atherogenesis and macrophages seem to be increased in abundance by diets low in magnesium. In addition, lipid peroxides inhibit lipoprotein lipase activity and thereby plasma triglyceride hydrolysis. Several studies have indicated a potential role of free radical participation in Mg deficiency lesions, the hypothesis being that Mg-deficiency decreases the natural defences to oxidative stress. Both leucotriene B4 and some lymphokines may play an important role in the skin damage found in Mg deficient dermatitis. SOD treatment20, which is known to be a scavenger of superoxide anion, prevents the cutaneous manifestation of Mg deficiency. An increased susceptibility in the liver of Mg-deficient rats to the damaging effect of CC14 and ethanol, was previously reported and lipid peroxidation has been implicated as a mechanism for these types of tissue damage21. Superoxide radicals are involved in the pathogenesis of ischaemic liver and the administration of SOD and Mg together improved survival rate following acute hepatic ischaemia and had a synergistic effect22. Other studies attempted to address the underlying mechanism of Mg deficiency-induced cardiomyopathy. The results demonstrate the protective properties of vitamin E23 and probucol against Mg deficiency-induced myocardial lesions in hamsters23. Moreover, these Mg-deficient animals showed an increased susceptibility to an in vivo oxidative stress24. Vitamin E administration was shown to protect against myocardial lesions following isoproterenol treatment. How Mg deficiency may contribute to enhanced lipid peroxidation is poorly understood. The free radical attack depends on the physical-chemical properties of substrates and is controlled by both an enzymatic (superoxide dismutase, catalase, glutathion peroxidase) and a non enzymatic (vitamin E) protective system. Imbalance between attack and defence can explain many pathological events19. In these events, the oxidative products of unsaturated fatty acids are of fundamental importance in particular those derived from arachidonic acid (Prostaglandins, prostacyclin, thromboxane, leukotrienes). These products are increased in Mg-deficient animals25. Vitamin E deficiency seems to decrease tissue magnesium levels in animals26 and a reduction in GSH biosynthesis has been demonstrated in Mg-deficient animals27. Moreover, an increased concentration of calcium intracellularly, which has been repeatedly demonstrated in Mg-deficient animalsl6, could theoretically act to enhance lipid peroxidation. Modifications in physico chemical properties of lipoproteins and membrane as indicated by chemical analysis and bulk fluidity14,15,16 may also be implicated in the increased susceptibility of these structures to lipid peroxidation. The disordering effect of Mg deficiency on lipid fluidity is the primary event followed by peroxidation of lipids which results in decreased fluidity28. Thus this secondary rigidifying effect may be of fundamental importance in the pathological consequences of chronic Mg deficiency.

Platelets and thrombosis

Several studies indicate that excess Mg inhibits platelet aggregation in vivo1,2. An increased susceptibility of platelets to thrombin-induced aggregation has been demonstrated in Mg-deficient rats6. The possibility exists that the marked hyperlipaemic effect of Mg deficiency affects platelet aggregation. There is also general agreement that Ca plays a key role in regulating platelet function and that platelet aggregation is triggered by a rise in the cytoplasmic Ca concentration. Platelets from Mg-deficient animals are less responsive to the aggregation-inhibiting effect of nifedipine than were platelets from control animals. These results suggest the possibility that magnesium deficiency is associated with increased cytosolic calcium in platelets29. The effect of Mg deficiency on thrombosis has also been reported. Injections of adrenaline at a dosage not affecting control rats induce the formation of huge thrombi in the left atrium of deficient animals1.

Cardiovascular lesions

The arterial damage resulting from Mg deficiency has been extensively reviewedl,2. This includes intimal thickening, thinning and fragmentation of the elastic membrane and calcification. An increase in the Ca content of the cardiovascular system occurs as a general consequence of Mg depletion. Early studies indicate that Mg deficiency enhances vascular lipid infiltration in rats, rabbits and monkeys on atherogenic dietsl,2. Recent studies confirm that Mg deficiency can intensify cardiovascular lipid deposition and lesions in animals on atherogenic diets and that dietary Mg supplementations prevents atherosclerosis30,31. These observations have led to the suggestion that Mg deficiency may be involved in the development of ischaemic heart disease32.

References

1. Rayssiguier, Y. & Gueux, E. (1986): Magnesium and lipids in cardiovascular disease. J. Am. Coll. Nutr. 5, 507-519.

2. Rayssiguier, Y. (1990): Magnesium and lipid metabolism. In Metal ions in biological systems, magnesium and its role in biology, nutrition and physiology, ed. H. Sigel, Vol. 26, pp. 341-358. New York: Marcel Dekker.

3. Rayssiguier, Y., Gueux, E. & Weiser, D. (1981): Effect of magnesium deficiency on lipid metabolism in rats fed a high carbohydrate diet. J. Nutr. 111, 1876-1883.

4. Rayssiguier, Y., Mazur, A., Cardot, P. & Gueux, E. (1989): Effects of magnesium on lipid metabolism and cardiovascular disease. In Magnesium in health and disease, eds. Y. Itokawa & J. Durlach, pp. 199-207. London: John Libbey.

5. Gueux, E., Mazur, A., Cardot, P. & Rayssiguier, Y. (1991): Effects of magnesium deficiency on plasma lipoprotein composition in rats. J. Nutr. 121, 1222-1227.

6. Rayssiguier, Y., Gueux, E., Cardot, P., Thomas, G., Robert, A. & Trugnan, G. (1986): Variations of fatty acid composition in plasma lipids and platelet aggregation in magnesium deficient rats. Nutr. Res. 6, 233-240.

7. Mahfouz, M.M. & Kummerow, A. (1989): Effect of magnesium deficiency on delta-6-desaturase activity and fatty acid composition of rat liver microsomes. Lipids 24, 727-732.

8. Mahfouz, M.M., Smith, T.L., Kummerow, A. (1989): Changes of linoleic acid metabolism and cellular phospholipid fatty acid composition in LLC-PK cells cultured at low magnesium concentrations. Biochim. Biophys. Acta 1006, 70-74.

9. Renaud, S., Ciavatti, M.,Thevenon, C.& Ripoll, J.P.(1983):Protective effectsof dietary calcium and magnesium on platelet function and atherosclerosis in rabbits fed saturated fat. Atherosclerosis 47, 187-198.

10. Durlach, J. (1988): Magnesium in clinical practice. London: John Libbey.

11. Brindley, D.N. & Rolland, Y. (1989): Possible connections between stress, diabetes, obesity, hypertension and altered lipoprotein metabolism that may result in atherosclerosis. Clin. Sci. 77, 453-461.

12. Rayssiguier, Y., Noé, L., Etienne, J., Gueux. E., Mazur, A. & Cardot, P. (1991): Effect of magnesium deficiency on post heparin lipase activity and tissue lipoprotein lipase. Lipids 26, 182-186.

13. Gueux, E., Rayssiguier, Y., Piot, M.C. & Alcindor, L. (1984): The reduction of plasma lecithine-cholesterol-acyltransferase activity by magnesium deficiency in the rat., J. Nutr. 114, 1479-1483.

14. Tongyai, S., Rayssiguier, Y., Motta, C., Gueux, E., Mauroist, P. & Heaton, F.W. (1989): Mechanism of the increased erythrocyte membrane fluidity during magnesium deficiency in weanling rats. Am. J. Phys. 257, C270-276.

15. Rayssiguier, Y., Gueux, E. & Motta, C. (1989): Evidence for a membrane modification in magnesium nutritional deficiency in the rat: fluorescence polarization study. Biomembrane & Nutr. (Colloques INSERM) 135, 441-452.

16. Rayssiguier, Y., Gueux, E. & Motta, C. (1991): Magnesium deficiency: effect on fluidity and function of plasma and subcellular membranes. In Magnesium: a relevant ion, eds. B. Lasserre & J. Durlach, pp. 311-319. London: John Libbey.

17. Freedman, A.M., Mak, I.T., Cassidy, M.M. & Weglicki, W.B. (1990): Magnesium deficient red blood cells exhibit an enhanced sensitivity to oxidative stress. Free radical biology and medicine, 9, (Suppl. 1), 119.

18. Hosakawa, Y., Yoshihara, T., Sato, I., Tojo, H., Niizeki, S. & Yamaguchi, K. (1989): The effect of magnesium deficiency on polymorphonuclear leucocyte function in rats. Magnesium Res. 2, 137.

19. Duthie, G.G., Wahle, W.J. & James, W.P.T. (1989): Oxidants, antioxidants and cardiovascular disease. Nutr. Res. Reviews 2, 51-62.

20. Hanada, K., Suzuki, S., Hashimoto, I., Sone, K. & Ishida, K. (1989): Aetiological role of leukotriene B4 and superoxide anion on magnesium deficiency dermatitis. Magnesium Res. 2, 19.

21. Rayssiguier, Y., Chevalier, F., Bonnet, M., Kopp, J. & Durlach, J. (1985): Influence of magnesium deficiency on liver collagen after carbon tetrachloride or ethanol administration to rats. J. Nutr. 115, 1656-1662.

22. Yu, S. & Flye, M.W. (1986): Superoxide dismutase (SOD) and magnesium chloride improved survival rate following acute hepatic ischemia. F.A.S.E.B.J. 45, A358.

23. Freedman, A,M., Atrakchi, A.H., Cassidy, M.M. & Weglicki, W.E. (1990): Magnesium deficiency-induced cardiomyopathy: protection by vitamin E. Biochem. Biophys. Res. Comm. 70, 1102-1106.

24. Freedman, A.M., Cassidy, M.M. & Weglicki, W.B. (1991): Magnesium deficient myocardium demonstrates an increased susceptibility to an in vivo oxidative stress. F.A.S.E.B.J. 5, A1309.

25. Masayoshi, S.,Cunnane,S.C.,Horrobin,D.F.,Manku,M.S.,Masanobu,H.& Michinobu H. (1988): Effects of low magnesium diet on the vascular prostaglandin and fatty acid metabolism in rats. Prostaglandins 36, 431-441.

26. Korpela,H. (1991):Hypothesis: Increased calcium and decreased magnesium in heart muscle and liver of pigs dying suddenly of microangiopathy (Mulberry heart disease): an animal model for the study of oxidative damage. J. Am. Coll. Nutr. 10, 127-131.

27. Mills, B.J.,Lindeman, R.D. & Lang, C.A. (1986): Magnesium deficiency inhibits biosynthesis of blood glutathione and tumor growth in the rat. Proc. Soc. Exp. Biol. Med. 181, 326-332.

28. Rice-Evans, C. & Hochstein. P. (1981): Alterations in erythrocyte membrane fluidity by phenylhydrazine induced peroxidation of lipids. B.B.R.C. 100, 1537-1542.

29. Rishi, M., Ahmad, A., Makheja, A., Karcher, D. & Bloom, S. (1990): Effects of reduced dietary magnesium on platelet production and function in hamsters. Lab Invest. 63, 717-721.

30. Altura. B.T., Brust, M., Bloom, S., Barbour, R.L., Stempak, J.G. & Altura, B.M. (1990): Magnesiuin dietary intake modulates blood lipid levels and atherogenesis. Proc. Nat. Acad. Sci. USA 87, 1840-1844.

31. Ouchi, Y.,Tabata, R.E., Stergiopoulos, K., Sato, F., Hattori, A. & Orimo, H. (1990): Effect of dietary magnesium on development of atherosclerosis in cholesterol fed rabbits. Arteriosclerosis 10, 732-737.

32. Rasmussen, H.S., Aurup, P., Goldstein, K., McNair, P., Mortensen, P.B., Larsen, O.G. & Lawaelz, H. (1989): Influence of magnesium substitution therapy on blood lipid composition in patients with ischemic heart disease. Arch. Intern. Med. 149, 1050-1053.


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