Glutathione
& Whey Proteins in
Stroke, Coronary, Cardiovascular, Heart Disease
Bioactive
Components of Whey and Cardiovascular Health (pdf)
Sharon K. Gerdes, Dr. W. James Harper, Ph.D, Dr. G. Miller, Ph.D.
(A Monograph Published by U.S. Dairy Export Council®)
Lowering
effect of dietary milk-whey protein v. casein on plasma and liver
cholesterol concentrations in rats
Zhang X, Beynen AC [Br J Nutr (1993 Jul) 70(1):139-46] The
effect of dietary whey protein versus casein on plasma and liver cholesterol
concentrations was investigated in female, weanling rats. Balanced,
purified diets containing either whey protein or casein, or the amino
acid mixtures simulating these proteins, were used. At the low dietary
protein level, whey protein versus casein did not affect plasma total
cholesterol, but lowered the concentration of liver cholesterol. At
the high dietary-protein level, whey protein significantly lowered
plasma and liver cholesterol and also plasma triacylglycerols. The
hypocholesterolemic effect of whey protein was associated with a decrease
in very-low-density-lipoprotein cholesterol. At the high dietary protein
concentration, whey protein reduced the fecal excretion of bile acids
when compared with casein. The effects of intact whey protein versus
casein were not reproduced by the amino acid mixtures simulating these
proteins. It is suggested tentatively that the cholesterol-lowering
effect of whey protein in rats is caused by inhibition of hepatic
cholesterol synthesis.
Serum
Glutathione in Adolescent Males Predicts Parental Coronary Heart Disease
John A. Morrison, PhD; Donald W. Jacobsen, PhD; Dennis L. Sprecher,
MD; Killian Robinson, MD; Philip Khoury, MS; Stephen R. Daniels, MD,
PhD [Circulation. 1999;100:2244] Traditional risk factors account
for only half of the morbidity and mortality from coronary heart disease
(CHD). There is substantial evidence that oxidative injury plays a
major role in the atherosclerotic process. Thus, antioxidants may
protect against development of atherosclerosis. Glutathione, an intracellular
tripeptide with antioxidant properties, may be protective. This study
found that low tGSH in adolescent boys is a significant independent
predictor of parental CHD, in addition to elevated LDL cholesterol,
low HDL cholesterol, and elevated total serum homocysteine concentrations.
Oxidant
stress in the vasculature
Maytin M,
Leopold J, Loscalzo J. [Curr Atheroscler Rep 1999 Sep;1(2):156-64]
Vascular disease and vasomotor responses are largely influenced by
oxidant stress. Numerous cellular antioxidant systems exist to defend
against oxidant stress; glutathione and the enzymes superoxide dismutase
and glutathione peroxidase are critical for maintaining the redox
balance of the cell. However, the redox state is disrupted by certain
vascular diseases. It appears that oxidant stress both promotes and
is induced by diseases such as hypertension, atherosclerosis, and
restenosis as well as by certain risk factors for coronary artery
disease including hyperlipidemia, diabetes, and cigarette smoking.
Once oxidant stress is invoked, characteristic pathophysiologic features
ensue, namely adverse vessel reactivity, vascular smooth muscle cell
proliferation, macrophage adhesion, platelet activation, and lipid
peroxidation.
Erythrocyte
susceptibility to lipid peroxidation in patients with coronary atherosclerosis
Dincer Y, Akcay T, and others. [Acta Med Okayama 1999
Dec;53(6):259-64.] "Erythrocyte TBARS production was significantly
higher in patients with coronary atherosclerosis than in the controls.
On the other hand, the levels of plasma high-density lipoproteins,
vitamin C, vitamin E and erythrocyte GSH were significantly lower,
and the levels of plasma total cholesterol, triglycerides, low-density
lipoproteins and TBARS were significantly higher in the patients with
coronary atherosclerosis than in the controls. In conclusion, our
results indicate that erythrocytes from patients with coronary atherosclerosis
are more susceptible to oxidation than those of controls and that
these patients have lowered antioxidant capacity as revealed by decreased
plasma levels of vitamins C and E."
L-2-oxothiazolidine-4-
carboxylic acid reverses endothelial dysfunction in patients with
coronary artery disease
Vita JA, Frei B, and others. [J Clin Invest 1998 Mar
15;101(6):1408-14.] "Cellular redox state...is a potential target
for therapy in patients with coronary artery disease." These data
suggest that augmenting cellular glutathione levels improves EDNO
action in human atherosclerosis. Cellular redox state may be an important
regulator of EDNO action, and is a potential target for therapy in
patients with coronary artery disease.
Glutathione
infusion enhances coronary blood flow during oxidative stress
[Circulation 1998;97:2299-2301] Oxygen free radicals cause endothelial
vasomotor dysfunction. Investigators found that reduced glutathione
intravenously suppresses constriction of human coronary arteries in
response to acetylcholine and increases the effect of nitroglycerin.
Glutathione administration may be useful in patients with coronary
artery disease, both as a result of improvement of endothelial dysfunction
and augmentation of nitroglycerin-induced vasodilation and antiplatelet
activity.
Serum glutathione in adolescent males predicts parental coronary heart
disease
Morrison JA, Jacobsen DW, Sprecher DL, Robinson K, Khoury P, Daniels
SR. [Circulation 1999 Nov 30;100(22):2244-7] There is substantial
evidence that oxidative injury plays a major role in the atherosclerotic
process. Thus, antioxidants may protect against development of atherosclerosis.
Glutathione, an intracellular tripeptide with antioxidant properties,
may be protective. This case-control study compared total serum glutathione
(tGSH) in 81 adolescent male offspring of parents with premature CHD
(ie, before 56 years of age) and 78 control male offspring of parents
without known or suspected CHD. Case offspring had significantly lower
tGSH than control offspring. Low tGSH in adolescent boys is a significant
independent predictor of parental CHD, in addition to elevated LDL
cholesterol, low HDL cholesterol, and elevated total serum homocysteine
concentrations.
Glutathione
reverses endothelial dysfunction and improves nitric oxide bioavailability
Prasad A, Andrews NP, Padder FA, Husain M, Quyyumi AA. [J Am
Coll Cardiol 1999 Aug;34(2):507-14] We investigated whether glutathione
(GSH), a reduced thiol that modulates redox state and forms adducts
of nitric oxide (NO), improves endothelium-dependent vasomotion and
NO activity in atherosclerosis. Endothelial dysfunction and reduced
NO activity are associated with atherosclerosis and its clinical manifestations
such as unstable angina. Thiol supplementation with GSH selectively
improves human endothelial dysfunction by enhancing NO activity.
Macrophage
foam cell formation during early atherogenesis is determined by the
balance between pro-oxidants and anti-oxidants in arterial cells and
blood lipoproteins
Aviram M. [Antioxid Redox Signal 1999 Winter;1(4):585-94]
Atherosclerosis is a multifactorial disease, where more than one mechanism,
along more than one step, contributes to macrophage cholesterol accumulation
and foam cell formation, the hallmark of early atherogenesis. Intervention
to inhibit LDL oxidation can affect the above additional LDL modifications.
The balance between pro-oxidants and anti-oxidants in the LDL particle,
as well as in arterial wall macrophages (such as NADPH oxidase vs.
glutathione), determines the extent of LDL oxidation. Antioxidants
can protect LDL from oxidation not only by their binding to the lipoprotein,
but also following their accumulation in cells of the arterial wall.....the
combination of antioxidants together with active paraoxonase decreases
the formation of Ox-LDL and preserves PON1's ability to hydrolyze
this atherogenic lipoprotein and hence, to attenuate atherosclerosis.
Hyperglycemia
in diabetic rats reduces the glutathione content in the aortic tissue
Tachi
Y, Okuda Y, Bannai C, Bannai S, Shinohara M, Shimpuku H, Yamashita
K, Ohura K. [Life Sci 2001 Jul 20;69(9):1039-47] The glutathione
redox cycle plays a major role in scavenging hydrogen peroxide (H2O2)
under physiological conditions. Recently, we demonstrated that a high
glucose concentration in the culture medium reduced the level of H2O2
scavenging activity of human vascular smooth muscle cells (hVSMCs).
We also showed that a high glucose concentration reduced the intracellular
glutathione (GSH) content and the rate of uptake of cystine, which
itself is a rate-limiting factor that maintains the GSH level. In
the present study, we investigated whether the hyperglycemic condition
in diabetic rats impairs the glutathione content in the aortic tissue
in vivo. We demonstrated in vivo that the hyperglycemic condition
in STZ-induced diabetic Wistar rats and OLETF rats reduced the GSH
content in aortic tissue. This suggested reduced glutathione redox
cycle function of aorta.
Effect
of administration of fermented milk containing whey protein concentrate
to rats and healthy men on serum lipids and blood pressure
Kawase M,
Hashimoto H, Hosoda M, Morita H, Hosono A. [J Dairy Sci 2000 Feb;83(2):255-63]
The effect of fermented milk supplemented with whey protein concentrate
on the serum lipid level of rats was investigated. The serum total
cholesterol level for the group fed fermented milk was significantly
lower than that of the control group in rats. After 8 wk, the high
density lipoprotein cholesterol level for the fermented milk group
showed a significant rise after 4 wk , whereas that of the placebo
group showed no change even after 4 wk. The triglyceride level for
the fermented milk group lowered significantly after 4 wk, whereas
that of the placebo group showed no change even after 4 wk. The atherogenic
index [(total cholesterol - high density lipoprotein cholesterol)/high-density
lipoprotein cholesterol] for the fermented milk group decreased significantly
from 4.24 to 3.52. The systolic blood pressure lowered significantly
by the intake of fermented milk. On the other hand, such effect was
not observed in the placebo group. These results indicate potential
of the development of fermented milk with multiple therapeutic effects.
Effect
of milk protein and fat intake on blood pressure and the incidence
of cerebrovascular diseases in stroke-prone spontaneously hypertensive
rats (SHRSP)
Ikeda K, Mochizuki S, Nara Y, Horie R, Yamori Y. [J Nutr Sci Vitaminol
(Tokyo) 1987 Feb;33(1):31-6] The intake of two milk protein-rich diets
containing casein and whey protein attenuated the development of severe
hypertension in stroke-prone spontaneously hypertensive rats (SHRSP),
and extended their life span in comparison with SHRSP on a regular
stock diet. Milk fat-rich diet intake reduced the incidence of cerebrovascular
disease in SHRSP without a significant fall in blood pressure. These
results suggest that certain milk components have a preventive effect
on hypertension and cerebrovascular disease in SHRSP.
Angiotensin
I-converting enzyme inhibitory properties of whey protein digests:
concentration and characterization of active peptides
Pihlanto-Leppala A, Koskinen P, Piilola K, Tupasela T, Korhonen H.
[J Dairy Res 2000 Feb;67(1):53-64] The aim of this study was to identify
whey-derived peptides with angiotensin I-converting enzyme (ACE) inhibitory
activity. The bovine whey proteins alpha-lactalbumin and beta-lactoglobulin
were hydrolysed with pepsin, trypsin, chymotrypsin, pancreatin, elastase
or carboxypeptidase alone and in combination. Whey protein digests
gave a 50% inhibition (IC50) of ACE activity at concentration ranges
within 345-1733 micrograms/ml. The IC50 values for the 1-30 kDa fractions
ranged from 485 to 1134 micrograms/ml and for the < 1 kDa fraction
from 109 to 837 mg/ml. Several ACE-inhibitory peptides were isolated
from the hydrolysates by reversed-phase chromatography, and the potencies
of the purified peptide fractions had IC50 values of 77-1062 microM.
The ACE-inhibitory peptides identified were alpha-lactalbumin fractions
(50-52), (99-108) and (104-108) and beta-lactoglobulin fractions (22-25),
(32-40), (81-83), (94-100), (106-111) and (142-146).
Lactokinins:
whey protein-derived ACE inhibitory peptides
FitzGerald RJ, Meisel H. [Nahrung 1999 Jun;43(3):165-7] Angiotensin-I-converting
enzyme (ACE) has been classically associated with the renin-angiotensin
system which regulates peripheral blood pressure. Peptides derived
from the major whey proteins, i.e. alpha-lactalbumin (alpha-la) and
beta-lactoglobulin (beta-lg) in addition to bovine serum albumin (BSA),
inhibit ACE. While they do not have the inhibitory potency of synthetic
drugs commonly used in the treatment of hypertension, these naturally
occurring peptides may represent nutraceutical /functional food ingredients
for the prevention/treatment of high blood pressure. Studies with
gastric and pancreatic proteinase digests of whey proteins indicate
that enzyme specificity rather than extent of hydrolysis dictates
the ACE inhibitory potency of whey hydrolysates.
Glutathione
deficiencies exacerbate response to stroke
Phyllis G. Paterson, University of Saskatchewan - Saskatoon.
Canada [Invited Symposium: The Therapeutic Potential of Phase II Enzyme
Induction] The cascade of events responsible for the death of neural
cells following a stroke include depletion of ATP, glutamate excitotoxicity,
calcium overload, and production of strong oxidants that can overwhelm
antioxidant defense. Glutathione (GSH) has a central role within the
finely tuned network of antioxidant systems that can respond to the
oxidative insult through its functions in peroxide scavenging via
glutathione-S-transferase and the family of glutathione peroxidases,
regeneration of alpha-tocopherol, and inhibition of NFkB which is
required for the expression of pro-inflammatory genes. Our laboratory
has used a nutritional approach to study the effects of GSH depletion
in a rat model of stroke. We have found that a deficiency of sulfur
amino acids used as a model of reduced cysteine supply for synthesis
depresses GSH concentration in a number of brain regions. A second
study demonstrated that acute sulfur amino acid deficiency exacerbates
brain damage in a rat model of global hemispheric hypoxic ischemia.
Approaches described in the literature for maintaining GSH under ischemia
conditions have also been targeted towards increasing its synthesis.
Administering a GSH ester immediately after an ischemic insult offered
neuroprotection in one study as did the delivery of N-acetylcysteine,
a compound that supports GSH synthesis by acting as a cysteine precursor.
The series of studies reviewed suggests that GSH is an important determinant
of the extent of secondary tissue damage in animal models of stroke.
Strategies to enhance GSH in brain should be tested for their therapeutic
efficacy in the human condition of stroke. (Funded by the Heart and
Stroke Foundation of Saskatchewan)
Milk
whey protein decreases oxygen free radical production in a murine
model of chronic iron-overload cardiomyopathy
Bartfay WJ, Davis MT, Medves JM, Lugowski S. [Can J Cardiol.
2003 Sep;19(10):1163-8.]
Chronic iron overload is a major cause of organ failure worldwide,
but its pathogenesis remains to be elucidated. Mice receiving iron
treatments with whey supplementation had significantly lower concentrations
of cytotoxic aldehydes and significantly higher cardiac levels of
GPx and GSH activity than did iron-only treated mice. Additional basic
research is warranted to examine the exact mechanisms by which milk
whey protein protects the heart.
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