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
excretion
9. 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
metabolism
2.
Adipose tissue and stress
Mg deficiency potentiates the
effect of stress since catecholamines release is increased in
Mg-deficient animals
1,2,10. Stress is a major
contributing factor to ill health, particularly cardiovascular
diseases and atherosclerosis, and there are possible connections
between stress and altered lipoprotein metabolism
11.
Mg deficiency enhances catecholamine secretion which results in
an increase in lipolysis and blood plasma magnesium has been
shown to decrease when lipolysis is increased
1,2.
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
animals
1,2.
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
impaired
1,2. 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
liver
4. 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 studies
12. 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 themselves
12. 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
transferase
13.
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 deficiency
14,15,16. 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 calcium
l6.
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 rats
7
(and unpublished data). Moreover Mg-deficient red blood cells
exhibit an enhanced sensitivity to oxidative stress when lipid
oxidation was determined by MDA formations
17. When the
effect of Mg deficiency on polymorphonuclear leukocyte function
in rats was examined, superoxide anion production was
significantly increased in deficient rats
18. 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
cells
19. 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 treatment
20,
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 CC1
4 and ethanol, was previously reported
and lipid peroxidation has been implicated as a mechanism for
these types of tissue damage
21. 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
effect
22. Other studies attempted to address the
underlying mechanism of Mg deficiency-induced cardiomyopathy. The
results demonstrate the protective properties of vitamin
E
23 and probucol against Mg deficiency-induced
myocardial lesions in hamsters
23. Moreover, these
Mg-deficient animals showed an increased susceptibility to an
in vivo oxidative stress
24. 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 events
19. 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
animals
25. Vitamin E deficiency seems to decrease
tissue magnesium levels in animals
26 and a reduction
in GSH biosynthesis has been demonstrated in Mg-deficient
animals
27. Moreover, an increased concentration of
calcium intracellularly, which has been repeatedly demonstrated
in Mg-deficient animals
l6, could theoretically act to
enhance lipid peroxidation. Modifications in physico chemical
properties of lipoproteins and membrane as indicated by chemical
analysis and bulk fluidity
14,15,16 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 fluidity
28. 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 rats
6. 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 platelets
29. 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
animals
1.
Cardiovascular lesions
The arterial damage resulting from
Mg deficiency has been extensively reviewed
l,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 diets
l,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 atherosclerosis
30,31. These
observations have led to the suggestion that Mg deficiency may be
involved in the development of ischaemic heart
disease
32.
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.
All articles by Dr. Durlach are copyrighted, and permission is
granted to Web users only to make single hard copies for personal
use. Additional reprints should be obtained from the originating
journals. Excerpts may be used by the media with attribution to
Dr. Durlach.
This page was first uploaded to The Magnesium Web Site on
August 5, 1997
http://www.mgwater.com/
Healthy Water
Association--USA