Inflammation, CR and health

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Hi All,

Four papers pertaining to how inflammation may affect a health

indicator, high

density lipoprotein (1) and how CR may affect " [m]yeloperoxidase

(MPO), a heme

protein existing in neutrophil and monocyte [] implicated in various

stages of

inflammatory conditions with the production of a variety of potent

oxidants " (2).

(1) is pdf-available.

Pertaining to (2), it may be relevant that dityrosine was involved

also and

" selective increase in o,o'-dityrosine levels and its prevention by a

life-prolonging caloric restriction regimen raise the possibility

that oxidation of

muscle proteins by tyrosyl radical contributes to the deterioration

of cardiac and

skeletal muscle function with advancing age " (3). (3) is pdf-

available.

Also pertaining to (2), (4) is a full-text available to all paper

that finds that a

third factor in the new CR/inflammation paper that is not pdf-

available, (2),

vascular cell adhesion molecule 1, is also affected by CR.

Inflammation modulation

is again involved, it seems.

Since CR appears to reduce inflammation, this may be our good news.

1. Fogelman AM.

News and Views

When good cholesterol goes bad.

Nat Med. 2004 Sep;10(9):902-3. No abstract available.

PMID: 15340411 [PubMed - indexed for MEDLINE]

High density lipoprotein (HDL) is often called the 'good

cholesterol.' Products of

an inflammatory enzyme, myeloperoxidase, are now shown to selectively

target the

main protein in HDL, apolipoprotein A-I. This turns the 'good

cholesterol' bad.

It has long been accepted that the more HDL cholesterol a person has,

the better off

he is. However, review of the data from the original Framingham

study, which first

solidly identified the importance of HDL, or of the data from the

placebo group in

another large study reveals that many heart attacks and strokes occur

in persons

with perfectly normal HDL cholesterol levels1. Several recent studies

have shown

that normal HDL is anti-inflammatory but HDL from patients with

cardiovascular

disease, or from patients with cardiovascular disease equivalents

such as diabetes,

is actually proinflammatory2, 3.

How HDL changes its properties and becomes proinflammatory has

remained largely a

mystery. In a recent issue of the Journal of Clinical Investigation,

Hazen and

colleagues4 solve much of the mystery. The authors report that the

inflammatory

enzyme myeloperoxidase selectively targets the main protein of HDL,

apolipoprotein

A-I (apoA-I). The consequence of this damage is that macrophages

associated with

atherosclerotic lesions retain increased amounts of cholesterol. As a

result, the

lesion is more lipid-rich, and hence more vulnerable to rupture, and

causes

thrombosis.

The new study emerges against a backdrop of provocative studies

showing that

proinflammatory or dysfunctional HDL has a high content of lipid

hydroperoxides3.

Administration of apoA-I to mice decreases lipid hydroperoxides and

converts

proinflammatory HDL to anti-inflammatory5, 6. Moreover,

administration of an oral

peptide (D-4F) that has many of the properties of apoA-I to a mouse

model of

atherosclerosis with particularly proinflammatory HDL appears to have

similar

effects as apoA-I, promoting reverse cholesterol transport from

macrophages7, 8 and

substantially reducing atherosclerosis7.

Hazen and colleagues asked what myeloperoxidase might have to do with

all of this.

The enzyme is abundant in macrophages in the inflammatory reaction of

the artery

wall that we call atherosclerosis. Using state-of-the-art mass

spectrometry, these

investigators report that myeloperoxidase-derived products modify

tyrosine amino

acids in apoA-I as much as 100-fold more than the same amino acid in

other proteins

found in human atherosclerotic lesions or in human plasma. The

chemical bonds and

structure of tyrosine make it particularly vulnerable to modification.

Additionally, the authors found that in patients with cardiovascular

disease, apoA-I

had substantially more tyrosines modified by the products of

myeloperoxidase than

controls, consistent with previous reports from the same group9, 10.

Extending their

previous work, they isolated apoA-I from human subjects with and

without

cardiovascular disease and demonstrated a remarkable inverse

relationship between

the amount of tyrosine in apoA-I modified by myeloperoxidase-derived

products and

the ability of HDL to remove cholesterol from macrophages. Thus, the

more tyrosine

in apoA-I that was modified by myeloperoxidase-derived products, the

less effective

the HDL was in removing cholesterol (Fig. 1).

Figure 1. Converting the HDL from anti-inflammatory to

proinflammatory.

(a) Normal HDL particle, containing two molecules of apoA-I, the

most abundant

protein component of HDL.

( Proinflammatory HDL particle. Hazen et al. show that

myeloperoxidase, an enzyme

abundant in macrophages at atherosclerotic lesions, selectively

damages apoA-I,

particularly at the amino acid tyrosine. This damage prompts

macrophages to retain

cholesterol. Other changes also occur in the particle, including an

overall

reduction in the amount of apoA-I, reductions in other components—

such as

paraoxonase, an enzyme that destroys oxidized lipids—and increases in

proinflammatory factors. Whether these other changes are related to

myeloperoxidase-induced damage is as yet unclear.

Using sophisticated studies with heavy isotopes, the authors

identified specific

areas of the apoA-I molecule that have a very high binding affinity

for the

myeloperoxidase enzyme. This affinity could explain why

myeloperoxidase-derived

products modify an extraordinary amount of apoA-I compared to other

proteins. These

modifications of apoA-I interfere with the ability of the molecule to

bind and

remove lipids, thus leading to increased lipid accumulation in the

arteries of

patients with cardiovascular disease.

Because the source of the modifying agents (myeloperoxidase products)

is the

macrophages in the atherosclerotic lesions, this constitutes a

positive feedback

loop to intensify the inflammation. The feedback loop probably

evolved to fight

infection and is now deleterious because there is no infecting agent.

In

cardiovascular disease, the inflammatory reaction is initiated by low

density

lipoprotein (LDL) & #8722;derived oxidized lipids that initiate the same

cascade of

cellular events as if there were an infectious agent present.

In animals, HDL is often the major source of plasma cholesterol. But

in adult humans

the major source of plasma cholesterol is not the apoA-I & #8722;containing

proteins

(HDL), but rather the apolipoprotein B (apoB) & #8722;containing lipoproteins

(LDL).

Throughout the particle's life in plasma, apoB remains with the

lipoprotein particle

to which it was originally attached. ApoB also has a heparin-binding

site that

causes apoB-containing proteins to avidly bind to the matrix in the

space just

beneath the single endothelial cell layer that lines the lumen of

arteries. As a

result, the concentration of apoB in even normal arteries is twice

that in plasma.

Unlike apoB, apoA-I does not stay with one particle, but moves from

one particle to

another. Normal apoA-I also does not have a heparin-binding site and

there is

normally more apoA-I in the plasma than in the arteries. But in

atherosclerotic

arteries, apoA-I accumulates in abundance11. Perhaps the accumulation

of apoA-I in

atherosclerotic arteries is related to myeloperoxidase-induced

changes in the

protein, which could make apoA-I able to tightly bind the artery wall.

Pharmaceutical companies are currently testing agents to raise HDL

cholesterol

levels in humans by blocking normal HDL metabolic pathways12. The

work cited here

suggests that this strategy, although it may raise HDL cholesterol

levels, may not

improve clinical outcomes as a single therapy. Statin therapy

modestly reduces

myeloperoxidase products in plasma9 and modestly improves the

inflammatory

properties of HDL3, but not to the levels seen in normal humans. The

combination of

statin therapy and therapy to raise HDL levels may prove useful if

the net effect is

to produce anti-inflammatory HDL. If the combination fails to render

the increased

HDL sufficiently anti-inflammatory, the combination may not

significantly improve

clinical outcomes.

REFERENCES

Navab, M. et al. J. Lipid Res. 45, 993 & #8722;1007 (2004).

Navab, M. et al. J. Lipid Res. 42, 1308 & #8722;1317 (2001).

Ansell, B.J. et al. Circulation 108, 2751 & #8722;2756 (2003).

Zheng, L. et al. J. Clin. Invest. 114, ' & #8722;yyy (2004).

Navab M. et al. J. Lipid Res. 41, 1481 & #8722;94 (2000).

Navab, M. et al. J. Lipid Res. 41, 1495 & #8722;1508 (2000).

Navab, M. et al. Circulation 105, 290 & #8722;292 (2002).

Navab, M. et al. Circulation 109, r120 & #8722;r125 (2004).

Shishehbor, M.H. et al. JAMA 289, 1675 & #8722;1680 (2003).

Brennan, M.L. et al. N. Engl. J. Med. 349, 1595 & #8722;1604 (2003).

Mackness, B., Hunt, R., Durrington, P.N. & Mackness, M.I.

Arterioscler. Thromb.

Vasc. Biol. 17, 1233 & #8722;1238 (1997).

Brousseau, M.E. et al. N. Engl. J. Med. 350, 1505 & #8722;1515 (2004).

2. Free Radic Res. 2005 Mar;39(3):283-9. Related Articles, Links

Aging effect on myeloperoxidase in rat kidney and its modulation by

calorie

restriction.

Gen Son T, Zou Y, Pal Yu B, Lee J, Young Chung H.

PMID: 15788232 [PubMed - in process]

Myeloperoxidase (MPO), a heme protein existing in neutrophil and

monocyte, is

implicated in various stages of inflammatory conditions with the

production of a

variety of potent oxidants. To investigate the extent of the

involvement of MPO in

aging, we measured MPO activities in kidney of rats at different ages

maintained

with an ad libitum (AL) or a calorie restriction (CR) dietary

regimen. Results

showed that the MPO activities increased during aging in AL rats, but

were

significantly attenuated by CR. This result was consistent with

altered protein

level of MPO during aging. In addition, we were able to detect

dityrosine that is a

stable end MPO-oxidation product. The amount of dityrosine increased

in old AL, but

not in old CR rats. To examine the source responsible for increased

MPO activity

during aging for leukocyte recruitment and infiltration, the levels

of vascular cell

adhesion molecule (VCAM-1) protein were measured. The level of VCAM-1

showed

age-dependent increase in AL rats, which was correlated with higher

activity of MPO

in old AL rats. Furthermore, we have found that LPS-induced

inflammation increased

the activity and protein levels of MPO, and VCAM-1 expression in

young rat kidneys.

These findings suggest that increased MPO activity with aging may

related to

increased recruitment of inflammatory cells, contributing to protein

oxidation

accumulation in the aging process. We propose that age-related

alterations of MPO,

dityrosine, and VCAM were modulated by CR through its anti-

inflammatory action.

3. Arch Biochem Biophys. 1997 Oct 1;346(1):74-80.

Caloric restriction attenuates dityrosine cross-linking of cardiac

and skeletal

muscle proteins in aging mice.

Leeuwenburgh C, Wagner P, Holloszy JO, Sohal RS, Heinecke JW.

PMID: 9328286 [PubMed - indexed for MEDLINE]

Oxidative damage, particularly to proteins, has been widely

postulated to be a major

causative factor in the loss of functional capacity during

senescence. The nature of

the various mechanisms that may contribute to protein oxidation is

only partially

understood. In this study, concentrations of two markers for

oxidative damage,

o,o'-dityrosine and o-tyrosine, were determined using stable isotope

dilution gas

chromatography-mass spectrometry in four tissues of the mouse, namely

heart,

skeletal muscle, brain, and liver, during youth (4 months old),

adulthood (14 months

old), and old (30 months old) age. A comparison was made between mice

that had

access to unlimited calories with those that were restricted to 60%

of the caloric

intake of the ad libitum regimen. Caloric restriction of this

magnitude extends the

average and maximum life span of mice by approximately 40%. In vitro

studies

demonstrated that o,o'-dityrosine was generated selectively in

proteins exposed to

tyrosyl radical. o-Tyrosine increased in proteins oxidized with

hydroxyl radical,

which also resulted in a variable increase in o,o'-dityrosine. In

mice fed ad

libitum, levels of o,o'-dityrosine increased with age in cardiac and

skeletal muscle

but not in liver or brain. In contrast, o-tyrosine levels did not

rise with age in

any of the tissues examined. These results suggest that tyrosyl

radical-induced

protein oxidation increases selectively with age in skeletal muscle

and heart.

Caloric restriction prevented the increase in o,o'-dityrosine levels

in cardiac and

skeletal muscle but did not influence o-tyrosine levels in any of the

four tissues.

This selective increase in o,o'-dityrosine levels and its prevention

by a

life-prolonging caloric restriction regimen raise the possibility

that oxidation of

muscle proteins by tyrosyl radical contributes to the deterioration

of cardiac and

skeletal muscle function with advancing age.

(4). Zou Y, Jung KJ, Kim JW, Yu BP, Chung HY.

Alteration of soluble adhesion molecules during aging and their

modulation by

calorie restriction.

FASEB J. 2004 Feb;18(2):320-2. Epub 2003 Dec 19.

PMID: 14688195 [PubMed - indexed for MEDLINE]

http://www.fasebj.org/cgi/reprint/03-0849fjev1

Al Pater