Mechanisms of Disease: macrophage-derived foam cells emerging as therapeutic targets in atherosclerosis

Abstract

The limited efficacy of current treatment strategies for targeting atherosclerosis and its complications requires new therapeutic options to be explored. From early fatty-streak lesions to advanced plaques, macrophage-derived foam cells are integral to the development and progression of atherosclerosis. Elucidation of molecular and cellular processes involving macrophages has led to numerous therapeutic targets being suggested. Potential sites of intervention range from monocyte recruitment, through cholesterol uptake and esterification, to cholesterol evacuation and macrophage egress from plaque. In addition, complex patterns of transcriptional regulation of genes involved in macrophage lipid homeostasis and in the regulation of inflammation have been partly unraveled. Recognition of ATP-binding cassette cholesterol transport mechanisms and cellular interactions with cholesterol-accepting apolipoproteins (or synthetic mimetics) opens up new potential therapies to induce atherosclerosis regression in humans. This review presents a systematic evaluation of actual and potential macrophage-directed pharmacologic interventions. It reflects the timely convergence of three important strands: advances in molecular and cell biology that have suggested therapeutic targets in macrophages; the development of multiple classes of drugs targeting these pathways; and the emergence of sensitive imaging techniques that have enabled identification of changes in plaque size and composition in response to treatment.

Silica nanoparticles induce oxidative stress, inflammation, and endothelial dysfunction in vitro via activation of the MAPK/Nrf2 pathway and nuclear factor-κB signaling

“…67 It can regulate the transmigration of adhered monocytes across the endothelial barrier into the subendothelial layer. 68 Despite belonging to macrophage-derived factor, MCP-1 mRNA expression in endothelial cells was significantly increased under SiNP exposure once the dosage was greater than 25 μg/mL. Our results suggest that SiNPs may have the potential to initiate monocyte recruitment, adhesion, and migration into the subendothelial layer of the intima, representing a considerable risk factor for promoting early events in the development of atherosclerosis.…”

The consequences of apoptosis in autoimmunity

“…Dysregulation of apoptosis has been associated with the pathogenesis of cancer [8,9], neurodegeneration [10], cardiovascular disease [11,12], and other complex diseases. The impact of apoptosis on immunity has been extensively investigated [2,13] and several reports suggest a correlation between apoptosis and autoimmunity through an impairment of apoptosis [14][15][16] or an ineffective removal of apoptotic cells [17][18][19][20].…”

Detecting and assessing macrophages in vivo to evaluate atherosclerosis noninvasively using molecular MRI

“…A large body of evidence implicates macrophages in the formation, progression, and pathogenicity of plaques (10). Monocytes from the peripheral circulation migrate into plaque and differentiate into macrophages, which in turn may engulf large quantities of low-density lipoprotein, turning into resident foam cells (11).…”