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Chapter 144 Atherothrombosis 2125

Chemokine
receptor
Adhesion
receptors
LDL Chemokine Foam cell
Monocyte migrating out

Plaque
Endothelium
Macrophage

LDL

ROS
Inracellular
lipid droplet Foam cell
PLA2
Scavenger receptors
(CD36, SRA, TLR)
OxLDL

Fig. 144.4 FOAM CELL FORMATION IS AN EARLY EVENT IN ATHEROGENESIS. LDL particles,
which are transudated through a dysfunctional endothelium at arterial branch points or areas of disrupted
shear, enter the intima and become trapped within the extracellular matrix. In the presence of inflammation,
the LDL particles become oxidized or otherwise modified and contribute to endothelial dysfunction by
interacting with receptors on endothelial cells, such as LOX1. Monocytes, in response to chemokines secreted
by activated endothelial cells and/or inflammatory leukocytes and platelets, adhere to the endothelium via
selectin family adhesion receptors, as well as β2 integrins and their counterreceptors (intercellular adhesion
molecule and vascular cell adhesion molecule). The monocytes then diapedese into the intima, where they
differentiate into inflammatory macrophages that generate oxidant stress within the vessel wall and release
proinflammatory mediators. Scavenger receptors, in particular CD36, expressed on macrophages recognize
and internalize oxLDL, leading to a feed-forward loop of increased LDL oxidation and increased scavenger
receptor expression, resulting ultimately in the formation of cholesterol-laden foam cells. These accumulate
in the intima, in part because of signals induced by oxLDL that inhibit migration, forming plaque. LDL,
Low-density lipoprotein; oxLDL, oxidized LDL; PLA2, phospholipase A2; ROS, reactive oxygen species; SRA,
scavenger receptor A1; TLR, Toll-like receptor.

now no longer recommend specific LDL cholesterol targets and The initial event in formation of the fatty streak and atheroscle-
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discourage use of nonstatin agents. A more recent trial of ezetimibe rotic plaque is most likely transudation of apoB-containing lipopro-
in combination with a statin, however, showed a 10% reduction in teins across the endothelial cell monolayer into the arterial wall (Fig.
cardiovascular events at 7 years associated with a mean decrease in 144.4). These lipoproteins are predominantly LDL, which is derived
LDL cholesterol of 16 mg/dL compared with statin alone. 10 by remodeling of VLDL particles secreted into the plasma by hepa-
Multiple epidemiologic and genetic studies have shown positive tocytes. So-called remnant lipoproteins derived from chylomicrons
associations of circulating triglyceride levels with coronary artery produced by the intestinal epithelium may also play a role. The
disease risk. Genetic variants in the gene encoding lipoprotein primary sites of lipoprotein entry are at arterial branch points or
lipase, a key regulator of triglyceride metabolism, have also been curvatures, explaining the discontinuous nature of atherosclerotic
associated with circulating triglyceride levels and with coronary artery lesions. These locations are where normal laminar blood flow is dis-
disease risk, as have genetic variants in the APOC3 and APOA5 turbed. Normal laminar flow activates a specific genetic “protection”
genes, which encode “minor” apolipoproteins in triglyceride-rich program in endothelial cells that enhances barrier function and
lipoproteins that critically regulate lipoprotein lipase in a reciprocal promotes an antiinflammatory, antioxidant, antiatherogenic pheno-
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manner. Therapeutic interventions targeting the lipoprotein lipase type. Loss of these shear-dependent signals disrupts the normal
pathway, including an APOC3 antisense oligonucleotide, are under endothelial architecture and increases permeability, allowing unregu-
development. lated entry of lipoproteins into the tunica intima. Within the intima
the lipoproteins become “trapped” by specific interactions with
normal components of the vessel wall, such as glycosoaminoglycans,
FOAM CELL FORMATION AND THE FATTY STREAK and undergo structural modifications, including aggregation, oxida-
tion, and, in settings of hyperglycemia, glycation.
Atherosclerotic plaques develop in a geographically discontinuous Just as data show an unequivocal role for LDL cholesterol in
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manner very slowly and continuously evolve over many decades. atherogenesis, equally compelling studies in humans and animal
Autopsy studies of motor vehicle accident victims showed early models show that mononuclear phagocytes are necessary for plaque
“preatherosclerotic” lesions present in the aorta of otherwise healthy formation and progression, and that atherosclerosis is associated with
young children. These small superficial lesions consist predominantly a chronic inflammatory state in the vessel wall and in the systemic
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of lipid-laden macrophages, so-called foam cells, and are termed fatty circulation. Targeted genetic mutations that block monocyte devel-
streaks. These are considered precursors of atherosclerotic plaque. opment from hematopoietic precursors or that prevent monocyte