Inflammation, Atherosclerosis, and Arterial Thrombosis: Role of The

ROY L. SILVERSTEIN, MD Chair, Department of Cell Biology, Cleveland Clinic, Cleveland, OH Infl ammation, atherosclerosis, and arterial thrombosis: Role of the scavenger receptor CD36 ABSTRACT • Tissue studies demonstrate that leukocytes and The CD36 scavenger receptor recognizes oxidized products of the infl ammatory system are prevalent in low-density lipoprotein (LDL) and cell-derived atherosclerotic plaque. • Animal models show an absence of athero- microparticles. It is expressed on macrophages and sclerosis in the absence of monocytes or monocyte platelets and is a mediator of both atherogenesis and recruitment as well as a crucial role for T-cell–derived thrombosis. Macrophages from CD36-null mice have a proinfl ammatory cytokines. defect in foam cell formation in response to exposure • It is becoming apparent that patients with to oxidized LDL, and CD36-null mice fed an athero- chronic systemic infl ammatory disorders (eg, sys- genic Western diet have signifi cantly less atheroscle- temic lupus erythematosus, Wegener granulomatosis, rosis than their wild-type counterparts. On platelets, chronic obesity, and aging) have increased risk of CD36 recognition of oxidized LDL contributes to their atherosclerosis. activation and provides a mechanistic link between This article examines the mechanisms by which hyperlipidemia, oxidant stress, and the prothrom- infl ammation promotes the development of athero- botic state. Cell-derived microparticles are also sclerosis and coronary artery disease, with particular major ligands for CD36 and contribute to thrombus attention to the role of CD36, a scavenger receptor for oxidized LDL. formation in a CD36-dependent manner even in the absence of hyperlipidemia. CD36 defi ciency in mice is associated with inhibition of thrombus formation OXIDATION IN PLAQUE FORMATION and with a reduction in microparticle accumulation in Prevailing models that link infl ammation to plaque thrombi. Targeting CD36 is a promising avenue for the formation suggest that infl ammatory stimuli (eg, ciga- treatment of atheroinfl ammatory disorders. rette smoke, hypertension) provoke changes in the phenotype of the cells of the arterial vessel wall that therosclerosis is recognized as a chronic allow penetration of leukocytes and LDL particles across the endothelial barrier, trapping them in the infl ammatory disorder of the vessel wall. Four 1,2 categories of evidence support the model of subendothelial space. An infl ammatory reaction atherosclerosis as an infl ammatory disease: then occurs in the subendothelial space involving A monocytes/macrophages and lymphocytes (especially • Biomarkers of infl ammation are clearly associated with risk and prognosis of atherosclerosis. Three T cells). Ultimately, through the production and that have been linked conclusively are: C-reactive release of oxidizing enzymes such as myeloperoxi- protein, myeloperoxidase (a marker of leukocyte acti- dase and nitric oxide synthase, the reaction leads to vation), and antibodies to oxidative modifi cations of generation of reactive oxygen and nitrogen species. low-density lipoprotein (LDL). In this setting, LDL particles become modifi ed to a form known as oxidized LDL (oxLDL). OxLDL loses its ability to bind to LDL receptors, which interferes Dr. Silverstein reported that he has no fi nancial interests or relationships that with its normal processing; perhaps more important, pose a potential confl ict of interest with this article. oxLDL gains an affi nity for a family of proteins called This article was developed from an audio transcript of Dr. Silverstein’s presen- scavenger receptors. Scavenger receptors on mac- tation at the 3rd Heart-Brain Summit. The transcript was formatted and edited by the Cleveland Clinic Journal of Medicine staff for clarity and conciseness, rophages bind and internalize the oxLDL particles, and was then reviewed, revised, and approved by Dr. Silverstein. leading to accumulation of cholesterol and other doi:10.3949/ccjm.76.s2.06 lipids in the cells. Over prolonged periods, increasing CLEVELAND CLINIC JOURNAL OF MEDICINE VOLUME 76 • SUPPLEMENT 2 APRIL 2009 S27 Downloaded from www.ccjm.org on September 24, 2021. For personal use only. All other uses require permission. INFLAMMATION, ATHEROSCLEROSIS, AND ARTERIAL THROMBOSIS quantities of oxLDL become internalized, leading to a lack of foam cell formation in vitro when cells formation of foam cells (lipid-laden macrophages), were exposed to oxLDL. Wild-type mice, in contrast, the precursor to atherosclerotic plaque. These lipid- showed foam cell formation after 12 to 24 hours.5 laden cells are more prone to apoptosis, which further To demonstrate in vivo relevance of these fi nd- contributes to plaque growth and rupture. ings, we crossed CD36-null mice with proatherogenic apoE-null mice. When fed an atherogenic Western CD36: A CRITICAL SCAVENGER RECEPTOR diet, apoE-null mice develop aortic atherosclerosis within several weeks, in a pattern and histology that One of the most critical scavenger receptors on closely resembles the human disease. In our experi- macrophages is CD36, which is a transmembrane ment, the mice that lacked both CD36 and apoE had glycoprotein that crosses the membrane twice. CD36 a dramatic decrease in the volume of atherosclerosis.5 is expressed heavily on monocytes, macrophages, Further studies showed that the proatherogenic role dendritic cells, fat, muscle, capillary endothelial of CD36 was highly likely mediated by the CD36 on cells, and platelets. It has multiple physiologic func- macrophages, since transplantation of bone marrow tions, including acting as a high-affi nity receptor for from CD36-null mice into apoE-null mice had the specifi c oxidized phospholipids that are found within same effect on atherosclerosis as seen in the apoE/ oxLDL.3 It is also a receptor for phosphatidyl serine CD36-double-null mice.6 (PS) and oxidized PS (oxPS) that is expressed on the Scavenger receptor–dependent formation and pro- surface of apoptotic cells. CD36 is highly conserved gression of atherosclerosis is supported by fi ndings of in evolution; orthologs are even found in fl ies, worms, an abundance of oxidized phospholipids that serve as and sponges. Evidence suggests that CD36 and other binding partners for CD36 in the plaque region of blood scavenger receptors probably evolved as part of the vessels, along with an absence of oxidized phospholip- innate immune system as recognition molecules for ids in the nonplaque region of blood. The enrichment pathogens and pathogen-infected cells.4 of oxidized phospholipid in the plaque allows CD36 to An interesting aspect of CD36 biology is that its penetrate the plaque, whereas removal of CD36 drasti- expression on macrophages is increased when the cally decreases the progression of atherosclerosis. 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 Platelet activation in the setting of hyperlipidemia as 9- and 13-hydroxy octadecadienoic acid (HODE). In addition to the formation and progression of plaque, These oxidized fatty acids are ligands for the nuclear CD36 may be involved in the terminal phases of ath- hormone receptor peroxisome proliferator–activated erosclerosis (ie, the thrombosis that occurs on a plaque) receptor (PPAR) gamma, a transcription factor as a result of abundant CD36 expression on platelets. that regulates expression of many genes, including CD36, in fact, was discovered as a platelet protein and CD36. Thus, oxLDL promotes increased expression named platelet glycoprotein IV, although for many years of CD36 and further cellular uptake of oxLDL. This the function of CD36 on platelets was not known. feed-forward loop presumably accelerates foam cell Recent studies by Podrez and colleagues, along with formation in the arterial neointima. Furthermore, our group, revealed that oxLDL binds to the surface CD36 expression is upregulated at the transcriptional of platelets in a concentration-dependent manner, level by infl ammatory cytokines such as granulocyte whereas normal LDL does not. The binding of oxLDL macrophage colony–stimulating factor (GM-CSF), to platelets can be blocked almost completely by inhib- macrophage colony–stimulating factor (M-CSF), iting CD36 with an antibody; binding did not occur and interleukin-4. Hyperglycemia increases CD36 with platelets obtained from CD36-defi cient mice or expression through a nontranscriptional mechanism people.7 Importantly, exposure to oxLDL caused plate- and may contribute to the proatherosclerotic state lets to be activated via a highly specifi c cell-signaling associated with diabetes. pathway; low concentrations of oxLDL, such as those found in plasma of individuals with even modest CD36 mediates atherogenesis hyperlipidemia, made platelets more sensitive to low The pathogenic role of oxLDL in atherosclerosis doses of “classic” platelet agonists such as collagen and is largely dependent on CD36. Studies using mac- adenosine diphosphate (ADP).8 These studies suggest rophages from genetically altered mice developed in that platelet CD36 could serve as a mechanistic link our laboratory that do not express CD36 demonstrated between infl ammation, oxidant stress, and hyperlipi- that absence of CD36 expression was associated with demia to create a prothrombotic state. S28 CLEVELAND CLINIC JOURNAL OF MEDICINE VOLUME 76 • SUPPLEMENT 2 APRIL 2009 Downloaded from www.ccjm.org on September 24, 2021. For personal use only. All other uses

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