Receptor-independent fluid-phase macropinocytosis promotes arterial foam cell formation and atherosclerosis

Accumulation of lipid-laden foam cells in the arterial wall plays a central role in atherosclerotic lesion development, plaque progression, and late-stage complications of atherosclerosis. However, there are still fundamental gaps in our knowledge of the underlying mechanisms leading to foam cell formation in atherosclerotic arteries. Here, we investigated the role of receptor-independent macropinocytosis in arterial lipid accumulation and pathogenesis of atherosclerosis. Genetic inhibition of fluid-phase macropinocytosis in myeloid cells (LysMCre+ Nhe1fl/fl) and repurposing of a Food and Drug Administration (FDA)–approved drug that inhibits macrophage macropinocytosis substantially decreased atherosclerotic lesion development in low-density lipoprotein (LDL) receptor–deficient and Apoe−/− mice. Stimulation of macropinocytosis using genetic (H-RASG12V) and physiologically relevant approaches promoted internalization of unmodified native (nLDL) and modified [e.g., acetylated (ac) and oxidized (ox) LDL] lipoproteins in both wild-type and scavenger receptor (SR) knockout (Cd36−/−/Sra−/−) macrophages. Pharmacological inhibition of macropinocytosis in hypercholesterolemic wild-type and Cd36−/−/Sra−/− mice identified an important role of macropinocytosis in LDL uptake by lesional macrophages and development of atherosclerosis. Furthermore, serial section high-resolution imaging, LDL immunolabeling, and three-dimensional (3D) reconstruction of subendothelial foam cells provide visual evidence of lipid macropinocytosis in both human and murine atherosclerotic arteries. Our findings complement the SR paradigm of atherosclerosis and identify a therapeutic strategy to counter the development of atherosclerosis and cardiovascular disease. Description Macrophage macropinocytosis plays an important role in atherosclerosis and is a key therapeutic target. Focusing on foam cell formation Macropinocytosis is a mechanism by which cells take up extracellular material. Here, Lin et al. investigated scavenger receptor–independent macropinocytosis in the development of atherosclerosis in mice. Inhibiting macropinocytosis by blocking Nhe1 prevented arterial lesion development in hypercholesterolemic mice, whereas stimulating macropinocytosis promoted foam cell formation and increased native low-density lipoprotein uptake in human macrophages in vitro. Myeloid depletion of Nhe1 suppressed macropinocytosis and atherosclerosis in mouse models, and repurposing imipramine, an antidepressant, similarly inhibited lipid accumulation in macrophages and attenuated atherosclerosis in mice. Results help identify a scavenger receptor–independent mechanism contributing to atherosclerosis and suggest a potential therapeutic approach.

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