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Comparative Medicine Clinical Research Center, Wake Forest University School of Medicine, Winston-Salem, NC
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INTRODUCTION |
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 TOP INTRODUCTION REFERENCES |
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). These beneficial effects of
soy protein on plasma lipoprotein concentrations culminated recently in
the U.S. Food and Drug Administration’s approval of a health claim
that "25 g of soy protein a day, as part of a diet low in saturated
fat and cholesterol, may reduce the risk of heart disease."
Additionally, various components of soy may modify cardiovascular
disease independently of effects on plasma lipoprotein concentrations.
Some of these potential lipid-independent mechanisms will be
described briefly. Genistein is known to bind rather weakly to the
classical estrogen receptor (ER
) but with much higher affinity,
i.e., ~85% of that of 17ß-estradiol, to ERß (Kuiper et al. 1998
). This suggests that genistein may have more potent
effects in tissues expressing ERß. Mäkelä et al. (1999)
recently published the results of a study in which they
measured expression of ER and ERß in the arteries of rats after
endothelial denudation, a technique that promotes atherogenesis. They
found that 7 d after arterial injury, expression of both ER and
ERß was increased, but ERß was overexpressed to a much greater
extent (~30 times more) than ER. In a second study, they treated
rats with various doses (0–2.5 mg/kg) of either 17ß-estradiol or
genistein administered subcutaneously after endothelial denudation.
With increasing doses of both 17ß-estradiol and genistein, there was
greater protection against neointima formation. Equivalent doses of
17ß-estradiol and genistein were equally effective in inhibiting
atherogenesis. These data suggest that ERß may play a role in
mediating some direct effect of genistein on the artery wall in the
prevention of atherosclerosis, that there is increasing protection at
higher doses and that the effects of genistein might be equal to
17ß-estradiol at equivalent doses.
In two published trials, soy protein isolate (SPI) with the isoflavones
has been shown to lower diastolic blood pressure in women. In the first
trial, a crossover study in 51 perimenopausal women, 20 g SPI
(containing 34 mg isoflavones) given in a split dose significantly
reduced diastolic blood pressure by 5 mm Hg (Washburn et al. 1999
). In a study by Crouse et al. (1999)
in
which moderately hypercholesterolemic men (n = 94) and
women (n = 62) were given supplements containing
25 g casein or 25 g SPI with different concentrations of
isoflavones (3–62 mg isoflavones per 25 g protein), there was a
significant trend for lower diastolic blood pressure with increasing
isoflavone dose in the women. There was no effect of the supplements on
blood pressure in men. Another finding in this study was that there was
a dose-response effect on plasma lipoproteins, i.e., higher
isoflavone doses resulted in lower total and LDL cholesterol
concentrations.
SPI with isoflavones has also been shown to improve vascular function
in both nonhuman and human primates. In a study in 11 female nonhuman
primates (Honoré et al. 1997
), consumption of SPI
with the isoflavones for 6 mo inhibited coronary artery vascular
constriction in response to acetylcholine (an endothelium-dependent
vascular response) by ~12% compared with a group fed
alcohol-washed (isoflavone-devoid) SPI. Further, an acute infusion
of genistein (30 min before testing) improved the vascular response of
the group fed the alcohol-washed SPI by ~9% compared with their
response before genistein. These same results have now been seen in
postmenopausal women (R. DuBroff and P. Decker, unpublished
observations). Women with abnormal endothelium-dependent,
flow-mediated dilation (n = 18), assessed by ultrasound
of the brachial artery after tourniquet release, were given a beverage
with 40 g soy protein containing 80 mg isoflavones daily for 1 mo
and then reassessed. Flow-mediated dilation was significantly
improved by 5.3% with soy consumption, and the response returned to
baseline after a 1-mo washout period. In a placebo-controlled,
randomized, crossover study with 21 peri- and postmenopausal women,
treatment for 5 wk with 80 mg/d of purified soy isoflavones improved
systemic arterial compliance, an indicator of vascular elasticity, by
26% (Nestel et al. 1997
). There was no effect of the
purified isoflavone treatment on LDL and HDL cholesterol
concentrations. Thus, soy protein isolate and, more specifically, the
isoflavones appear to have beneficial effects on the endothelium and
vascular function, and the effects appear to be independent of effects
on plasma lipoproteins.
Another important mechanism by which soy isoflavones might improve
cardiovascular disease is the effect they have on platelets. In a study
with 12 female nonhuman primates, a group fed SPI without the
isoflavones had a 26% greater reduction in blood flow after
collagen-induced platelet activation than did a group fed SPI with
the isoflavones (Williams and Clarkson 1998
). Although
the precise mechanism for this protection against reduction in blood
flow by the isoflavones could not be determined in this study, there
are several possible explanations. When platelets are activated, they
release their vasoactive substances including serotonin, which is a
potent vasoconstrictor. Williams and Clarkson (1998)
found that in vitro platelet aggregation in response to thrombin and
serotonin was reduced in platelets collected from animals fed SPI with
the isoflavones compared with platelets from animals fed the
alcohol-washed SPI. Similarly, Schoene and Guidry (1999)
found that platelets from rats fed isoflavone-intact
SPI had apparent volumes that were significantly smaller than platelets
from rats fed isoflavone-devoid SPI, suggesting that these smaller
platelets were in a more quiescent state. Other indicators of platelet
activation in that study also suggested that the isoflavones could
inhibit platelet activation. Helmeste and Tang (1995)
found that genistein inhibited serotonin uptake in platelets. Thus the
isoflavones might inhibit platelet activation and aggregation and
reduce the amount of serotonin in the platelets, all of which could
contribute to a reduction in coronary vasospasm and thrombosis.
SPI and the isoflavones in soy in particular have been shown to be
antioxidants in numerous studies. Tikkanen et al. (1998)
studied the effects of feeding soy protein containing 60 mg isoflavones
per day on LDL oxidation in a group of six healthy volunteers. They
measured copper-induced LDL oxidation during a baseline period,
after 2 wk of soy consumption and then after a 2-wk washout period.
They found that soy treatment significantly prolonged LDL oxidation lag
time by ~20 min. In a study in 46 surgically postmenopausal nonhuman
primates, arterial lipid peroxidation levels were lower by ~17% in
the group fed SPI with the isoflavones compared with the group fed
casein and lactalbumin as the protein source (Wagner et al. 1997
). These studies suggest that soy with the isoflavones can
reduce the susceptibility of LDL particles to oxidation and that this
has implications for the development of atherosclerosis.
Studies done in vitro have suggested that the isoflavones also affect
smooth muscle cells that are involved in atherosclerosis promotion and
progression. Genistein was reported to inhibit the migration and
proliferation of smooth muscle cells (Fujio et al. 1993
,
Mäkelä et al. 1999
, Shimokado et al. 1994
and 1995
).
There are many mechanisms by which soy protein, the isoflavones or both might decrease atherosclerosis and cardiovascular disease. There are the well-recognized improvements in plasma lipid and lipoprotein concentrations (i.e., lower LDL cholesterol, lower triglycerides and, possibly, higher HDL cholesterol). There is also evidence that soy protein, isoflavones or both can have beneficial effects on the following: blood pressure; vascular and endothelial cell function; platelet activation, aggregation and serotonin storage; LDL oxidation; smooth muscle cell proliferation and migration; and possibly ERß-mediated direct effects on inhibition of atherogenesis. However, whether soy consumption can reduce cardiovascular disease morbidity and mortality remains an unanswered question.
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FOOTNOTES |
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REFERENCES |
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TOPINTRODUCTIONREFERENCES |
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1.
Anderson J. W., Johnstone B. M., Cook-Newell M. E. Meta-analysis of the effects of soy protein intake on serum lipids. N. Engl. J. Med. 1995;333:276-282
2.
Crouse J. R., Morgan T. M., Terry J. G., Ellis J., Vitolins M., Burke G. L. A randomized trial comparing the effect of casein with that of soy protein containing varying amounts of isoflavones on plasma concentrations of lipids and lipoproteins. Arch. Intern. Med. 1999;159:2070-2076
3. Fujio Y., Fumiko Y., Takahashi K., Shibata N. Responses of smooth muscle cells to platelet-derived growth factor are inhibited by herbimycin-A tyrosine kinase inhibitor+. Biochem. Biophys. Res. Commun. 1993;195:79-83[Medline]
4. Helmeste D. M., Tang S. W. Tyrosine kinase inhibitors regulate serotonin uptake in platelets. Eur. J. Pharmacol. 1995;280:R5-R7[Medline]
5. Honoré E. K., Williams J. K., Anthony M. S., Clarkson T. B. Soy isoflavones enhance vascular reactivity in atherosclerotic female macaques. Fertil. Steril. 1997;67:148-154[Medline]
6.
Kuiper G.G.J.M., Lemmen J. G., Carlsson B., Corton J. C., Safe S. H., van der Saag P. T., van der Burg B., Gustafsson J.-Å. Interaction of estrogenic chemicals and phytoestrogens with estrogen receptor ß. Endocrinology 1998;139:4252-4263
7.
Mäkelä S., Savolainen H., Aavik E., Myllärniemi M., Strauss L., Taskinen E., Gustafsson J.-\, A. & Häyry P. Differentiation between vasculoprotective and uterotrophic effects of ligands with different binding affinities to estrogen receptors and ß. Proc. Natl. Acad. Sci. U.S.A. 1999;96:7077-7082
8.
Nestel P. J., Yamashita T., Sasahara T., Pomeroy S., Dart A., Komesaroff P., Owen A., Abbey M. Soy isoflavones improve systemic arterial compliance but not plasma lipids in menopausal and perimenopausal women. Arterioscler. Thromb. Vasc. Biol. 1997;17:3392-3398
9. Schoene N. W., Guidry C. A. Dietary soy isoflavones inhibit activation of rat platelets. J. Nutr. Biochem. 1999;10:421-426
10. Shimokado K., Umezawa K., Ogata J. Tyrosine kinase inhibitors inhibit multiple steps of the cell cycle of vascular smooth muscle cells. Exp. Cell Res. 1995;220:266-273[Medline]
11.
Shimokado K., Yokota T., Umezawa K., Sasaguri T., Ogata J. Protein tyrosine kinase inhibitors inhibit chemotaxis of vascular smooth muscle cells. Arterioscler. Thromb. 1994;14:973-981
12.
Tikkanen M. J., Wahala K., Ojala S., Vihma V., Adlercreutz H. Effect of soybean phytoestrogen intake on low density lipoprotein oxidation resistance. Proc. Natl. Acad. Sci. U.S.A. 1998;95:3106-3110
13. Wagner J. D., Cefalu W. T., Anthony M. S., Litwak K. N., Zhang L., Clarkson T. B. Dietary soy protein and estrogen replacement therapy improve cardiovascular risk factors and decrease aortic cholesteryl ester content in ovariectomized cynomolgus monkeys. Metabolism 1997;46:698-705[Medline]
14. Washburn S., Burke G. L., Morgan T., Anthony M. Effect of soy protein supplementation on serum lipoproteins, blood pressure, and menopausal symptoms in perimenopausal women. Menopause 1999;6:7-13[Medline]
15. Williams J. K., Clarkson T. B. Dietary soy isoflavones inhibit in-vivo constrictor responses of coronary arteries to collagen-induced platelet activation. Coron. Artery Dis. 1998;9:759-764[Medline]
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