Abstract
Folate receptor β (FR-β) is overexpressed on activated, but not resting, macrophages involved in a variety of inflammatory and autoimmune diseases. A pivotal step in atherogenesis is the subendothelial accumulation of macrophages. In nascent lesions, they coordinate the scavenging of lipids and cellular debris to define the likelihood of plaque inflammation and eventually rupture. In this study, we determined the presence of FR-β-expressing macrophages in atherosclerotic lesions by the use of a fluorine-18-labeled folate-based radiotracer. Human endarterectomized specimens were used to measure gene expression levels of FR-β and CD68. Increased FR-β and CD68 levels were found in atherosclerotic plaques compared to normal artery walls by quantitative real-time polymerase chain reaction. Western blotting and immunohistochemistry demonstrated prominent FR-β protein levels in plaques. FR-β-positive cells colocalized with activated macrophages (CD68) in plaque tissue. Carotid sections incubated with 3'-aza-2'-[18F]fluorofolic acid displayed increased accumulation in atherosclerotic plaques through in vitro autoradiography. Specific binding of the radiotracer correlated with FR-β-expressing macrophages. These results demonstrate high FR-β expression in atherosclerotic lesions of human carotid tissue correlating with CD68-positive macrophages. Areas of high 3'-aza-2'-[18F]fluorofolic acid binding within the lesions represented FR-β-expressing macrophages. Selectively targeting FR-β-positive macrophages through folate-based radiopharmaceuticals may be useful for noninvasive imaging of plaque inflammation.
Highlights
Folate receptor b (FR-b) is overexpressed on activated, but not resting, macrophages involved in a variety of inflammatory and autoimmune diseases
A THEROSCLEROSIS, a progressive inflammatory disease, plays a key role in the pathogenesis of cardiovascular diseases.[1]. It is characterized by thickening of the artery walls due to accumulation of lipids and fibrous elements in the tunica intima leading to the formation of atherosclerotic plaques
We addressed the questions whether (1) expression levels of human folate receptor (FR)-b differ between plaques of stable and vulnerable appearance and (2) whether our recently developed 18F-labeled folate-based radiotracer, 39aza-29-[18F]fluorofolic acid,[23] binds to human atherosclerotic plaques
Summary
Folate receptor b (FR-b) is overexpressed on activated, but not resting, macrophages involved in a variety of inflammatory and autoimmune diseases. Specific binding of the radiotracer correlated with FR-b-expressing macrophages These results demonstrate high FR-b expression in atherosclerotic lesions of human carotid tissue correlating with CD68-positive macrophages. # 2014 Decker Publishing that promote the recruitment and proliferation of other cells.[2] Matrix metalloproteinases (MMP), reactive oxygen species, and proinflammatory cytokines such as tumor necrosis factor a (TNF-a) provoke plaque destabilization, which makes it prone to rupture. These advanced plaques, so-called vulnerable plaques, can lead to serious thrombotic events, comprising the risk of initiating myocardial infarction or stroke.[3,4,5]. Exploiting the fact that activated macrophages but not resting macrophages or other immune cells overexpress the folate receptor (FR) could be of clinical significance with regard to the diagnosis and therapy of inflammatory diseases.[6]
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