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2286 Part XII: Hemostasis and Thrombosis Chapter 134: Atherothrombosis: Disease Initiation, Progression, and Treatment 2287

Lipid Peroxidation and Atherosclerosis and cholesterol accumulation via upregulation of macrophage scaven-
Macrophages control the amount of cholesterol loading by downreg- ger receptors and reduction in reverse cholesterol transport. Thus, gut
ulating the native LDL receptor. Therefore, knowing how cholesterol microbiota may accelerate atherosclerosis risk.
is taken up into macrophages is important. Cell culture experiments
revealed a “foam cell paradox,” in which macrophages engulf only mod-
ified lipids. Treatment of native LDL with copper or acetic anhydride Accumulation of Low-Density Lipoprotein in the
(causing acetylation) led to increased LDL uptake through use of the Vascular Wall
scavenger receptor, leading to the formation of lipid-laden macrophages. Three potential factors lead to accumulation of LDL in the vascular wall:
These experiments led to the peroxidation theory of atherosclerosis, increased permeability of the endothelium, prolonged retention of lipo-
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whereby LDL modification is an essential step in the development of proteins in the intima, and slow removal of lipoproteins from the vessel
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foam cells. Although the precise mechanisms responsible for LDL oxi- wall. Rabbits fed a high-cholesterol diet develop aortic wall lesions
dation remain unclear, enzymes including myeloperoxidase, inducible at specific lesion-susceptible sites; however, endothelial permeability is
NO synthase, and NADPH oxidases are involved in the process. 99,100 Of not increased at those sites, indicating that LDL is selectively retained in
note, macrophages express each of these enzymes, which normally are these regions. 119,120 Retention of LDL molecules likely results from their
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used as antimicrobial reactive oxygen species essential for innate immu- adherence to proteoglycans in the vessel wall. LDL genetically engi-
nity. Thus, accumulation of cholesterol in the macrophage occurs via neered to not bind to proteoglycans is hypothesized to be less athero-
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scavenger (not LDL) receptors of oxidized (and not native) LDL. Mye- genic than native LDL. 20
loperoxidase is an enzyme thought to cause lipid peroxidation in the Oxidized LDL and its products, oxidized phospholipids and
intimal space and circulating levels are associated with adverse clinical oxysterols, have other properties that make them potentially proathero-
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outcomes in the setting of acute coronary syndromes and predictive of genic. These properties include proinflammatory characteristics,
major adverse cardiovascular events. 99 such as chemotactic signaling for monocytes, smooth muscle cells, and
T lymphocytes (but not for B lymphocytes or neutrophils, neither of
which is found in lesions) and increased expression of VCAM-1 on,
Scavenger Receptors and Atherosclerosis 123
Conserved pattern recognition receptors expressed by macrophages and stimulation of CCL2 release from, endothelial cells. Oxidized
include scavenger receptors A and B1 and CD36, all of which internalize LDL also may contribute to instability of the atherosclerotic plaque via
oxidized LDL. 102,103 Macrophages express various genes in response to induction of type 1 metalloproteinase expression and increase in TF
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oxidized LDL, including peroxisome proliferator-activated receptor-γ activity. For oxidized LDL to be a ligand for the scavenger receptor,
and adenosine triphosphate–binding cassette transporter A1, which extensive degradation of the polyunsaturated fatty acid in the sn-2 posi-
profoundly influence macrophage-mediated inflammation and athero- tion of phospholipids by oxidation is essential.
sclerotic activity. To test the oxidized LDL hypothesis, several clinical studies have
Cell culture studies indicate that scavenger receptor A recognizes been conducted using antioxidant vitamins, most commonly vitamin E;
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acetylated LDL but, unlike the LDL receptor, is not downregulated in however, most of the completed studies gave negative results. At the
response to increased cholesterol content and thus likely accounts for present time, treatment with vitamin E does not appear to be beneficial
foam cell formation. However, no evidence indicates that acetyl LDL in preventing cardiovascular events.
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is generated in vivo, indicating other modifications of LDL, such as oxi-
dation, may be required for foam cell formation. 105,106 Another scaven- High-Density Lipoprotein and Atherosclerosis
ger receptor presumed to be involved in the atherosclerotic process is A low level of HDL cholesterol is a strong predictor of adverse cardiovas-
CD36, a receptor that avidly binds oxidized LDL. cular events, presumably because the low level is associated with insuf-
Circulating IgG and IgM antibodies against products of lipid per- ficient reverse cholesterol transport. Animal studies using liver-directed
oxidation are present in the plasma of animals and humans. These gene transfer of human apoA–apoI resulted in significant promotion of
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antibodies closely correlate with measures of lipid peroxidation and reverse cholesterol transport and regression of preexisting atheroscle-
with atherosclerotic progression and regression in murine models. rotic lesions in LDL receptor-deficient mice. 127,128 The HDL level may
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Immunization of hypercholesterolemic rabbits and mice with products not be as important as amount of reverse cholesterol transport. For
of oxidized LDL, such as malonyldialdehyde LDL or copper-oxidized example, the capacity of HDL to accept cholesterol from macrophages
LDL, inhibits the progression of atherosclerotic lesion formation. 109–112 is predictive of atherosclerotic burden. However, HDL has additional
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These experiments have been interpreted to indicate that an immuno- antiatherogenic properties that may confer protection against athero-
logic response to oxidized LDL components can alter the atheroscle- sclerosis. For example, HDL is protective against oxidation of LDL,
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rotic process. at least in part because of paraoxonase, an enzyme physically associated
Leukocyte-derived 5-lipoxygenase also contributes to atheroscle- with HDL that degrades organophosphates. Paraoxonase polymor-
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rosis susceptibility in mice. Animal studies indicate the importance of phisms are associated with increased risk of CVD, also indicating that
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lipoxygenases in atherosclerosis as disruption of the 12,15-lipoxygenase oxidized LDL is an important factor in atherosclerotic development. 132
gene diminishes atherosclerosis in apoE-deficient mice, and overex- Research studies currently are evaluating novel ways to increase
pression of 15-lipoxygenase in vascular endothelium accelerates early HDL levels or to use apoA–apoI variants and mimetics that hopefully
atherosclerosis in LDL receptor-deficient mice. 114,115 This enzyme is will cause regression of atherosclerosis. So far, initial clinical studies
under study as a potential target to inhibit the atherosclerotic process. 116 were not successful. Cholesteryl ester transfer protein promotes the
Gut Microbiome There are newer data indicating that intes- transfer of cholesteryl esters from antiatherogenic HDLs to proathero-
tinal microbes are involved in cardiometabolic diseases. Systemic genic apoB-containing lipoproteins, including very-low-density lipo-
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inflammation is activated is the setting of chronic bacterial transloca- proteins (VLDLs), VLDL remnants, intermediate-density lipoproteins,
tion (secondary to increased intestinal permeability) leading to mac- and LDLs. A deficiency of this molecule results in increased HDL levels
rophage influx into adipose tissue resulting in insulin resistance and and decreased LDL levels, a lipid profile that is antiatherogenic. A large
nonalcoholic fatty liver disease. The increased inflammation may also clinical study in humans showed that inhibition of the transfer protein
be secondary to trimethylamine-N-oxide via influx of macrophages with torcetrapib increased HDL levels but was associated with increased

Kaushansky_chapter 134_p2281-2302.indd 2287 17/09/15 3:49 pm