Atherosclerosis is recognized as a chronic inflammatory disorder of the vessel wall. Four categories of evidence support the model of atherosclerosis as an inflammatory disease:
- Biomarkers of inflammation are clearly associated with risk and prognosis of atherosclerosis. Three that have been linked conclusively are: C-reactive protein, myeloperoxidase (a marker of leukocyte activation), and antibodies to oxidative modifications of low-density lipoprotein (LDL).
- Tissue studies demonstrate that leukocytes and products of the inflammatory system are prevalent in atherosclerotic plaque.
- Animal models show an absence of atherosclerosis in the absence of monocytes or monocyte recruitment as well as a crucial role for T-cell–derived proinflammatory cytokines.
- It is becoming apparent that patients with chronic systemic inflammatory disorders (eg, systemic lupus erythematosus, Wegener granulomatosis, chronic obesity, and aging) have increased risk of atherosclerosis.
This article examines the mechanisms by which inflammation promotes the development of atherosclerosis and coronary artery disease, with particular attention to the role of CD36, a scavenger receptor for oxidized LDL.
OXIDATION IN PLAQUE FORMATION
Prevailing models that link inflammation to plaque formation suggest that inflammatory stimuli (eg, cigarette smoke, hypertension) provoke changes in the phenotype of the cells of the arterial vessel wall that allow penetration of leukocytes and LDL particles across the endothelial barrier, trapping them in the subendothelial space.1,2 An inflammatory reaction then occurs in the subendothelial space involving monocytes/macrophages and lymphocytes (especially T cells). Ultimately, through the production and release of oxidizing enzymes such as myeloperoxidase and nitric oxide synthase, the reaction leads to generation of reactive oxygen and nitrogen species. In this setting, LDL particles become modified to a form known as oxidized LDL (oxLDL). OxLDL loses its ability to bind to LDL receptors, which interferes with its normal processing; perhaps more important, oxLDL gains an affinity for a family of proteins called scavenger receptors. Scavenger receptors on macrophages bind and internalize the oxLDL particles, leading to accumulation of cholesterol and other lipids in the cells. Over prolonged periods, increasing quantities of oxLDL become internalized, leading to formation of foam cells (lipid-laden macrophages), the precursor to atherosclerotic plaque. These lipidladen cells are more prone to apoptosis, which further contributes to plaque growth and rupture.
CD36: A CRITICAL SCAVENGER RECEPTOR
One of the most critical scavenger receptors on macrophages is CD36, which is a transmembrane glycoprotein that crosses the membrane twice. CD36 is expressed heavily on monocytes, macrophages, dendritic cells, fat, muscle, capillary endothelial cells, and platelets. It has multiple physiologic functions, including acting as a high-affinity receptor for specific oxidized phospholipids that are found within oxLDL.3 It is also a receptor for phosphatidyl serine (PS) and oxidized PS (oxPS) that is expressed on the surface of apoptotic cells. CD36 is highly conserved in evolution; orthologs are even found in flies, worms, and sponges. Evidence suggests that CD36 and other scavenger receptors probably evolved as part of the innate immune system as recognition molecules for pathogens and pathogen-infected cells.4
An interesting aspect of CD36 biology is that its expression on macrophages is increased when the cells are exposed to oxLDL. Among the changes that occur in the lipid components of LDL when it is oxidized is the formation of oxidized fatty acids such as 9- and 13-hydroxy octadecadienoic acid (HODE). These oxidized fatty acids are ligands for the nuclear hormone receptor peroxisome proliferator–activated receptor (PPAR) gamma, a transcription factor that regulates expression of many genes, including CD36. Thus, oxLDL promotes increased expression of CD36 and further cellular uptake of oxLDL. This feed-forward loop presumably accelerates foam cell formation in the arterial neointima. Furthermore, CD36 expression is upregulated at the transcriptional level by inflammatory cytokines such as granulocyte macrophage colony–stimulating factor (GM-CSF), macrophage colony–stimulating factor (M-CSF), and interleukin-4. Hyperglycemia increases CD36 expression through a nontranscriptional mechanism and may contribute to the proatherosclerotic state associated with diabetes.
CD36 mediates atherogenesis
The pathogenic role of oxLDL in atherosclerosis is largely dependent on CD36. Studies using macrophages from genetically altered mice developed in our laboratory that do not express CD36 demonstrated that absence of CD36 expression was associated with a lack of foam cell formation in vitro when cells were exposed to oxLDL. Wild-type mice, in contrast, showed foam cell formation after 12 to 24 hours.5
To demonstrate in vivo relevance of these findings, we crossed CD36-null mice with proatherogenic apoE-null mice. When fed an atherogenic Western diet, apoE-null mice develop aortic atherosclerosis within several weeks, in a pattern and histology that closely resembles the human disease. In our experiment, the mice that lacked both CD36 and apoE had a dramatic decrease in the volume of atherosclerosis.5 Further studies showed that the proatherogenic role of CD36 was highly likely mediated by the CD36 on macrophages, since transplantation of bone marrow from CD36-null mice into apoE-null mice had the same effect on atherosclerosis as seen in the apoE/CD36-double-null mice.6
Scavenger receptor–dependent formation and progression of atherosclerosis is supported by findings of an abundance of oxidized phospholipids that serve as binding partners for CD36 in the plaque region of blood vessels, along with an absence of oxidized phospholipids in the nonplaque region of blood. The enrichment of oxidized phospholipid in the plaque allows CD36 to penetrate the plaque, whereas removal of CD36 drastically decreases the progression of atherosclerosis.