Abstract
During atherosclerosis, low density lipoproteins (LDL) accumulate in the arteries, where they become modified, aggregated and retained. Such deposits of aggregated LDL (agLDL) can be recognized by macrophages, which attempt to digest and clear them. AgLDL catabolism promotes internalization of cholesterol and foam cell formation, which is an important component of atherosclerosis. Characterization and therapeutic blockade of this process will likely delay disease progression. When macrophages interact with agLDL in vitro, they form a novel extracellular, hydrolytic compartment, the lysosomal synapse, aided by local actin polymerization to digest agLDL. Here, we demonstrate in vivo that atherosclerotic plaque macrophages contacting cholesterol rich LDL deposits polymerize actin and form a strikingly similar compartment. Live cell imaging revealed macrophage cortical F‐actin depolymerization driven by PIP2 hydrolysis occurs in parallel to actin polymerization at the lysosomal synapse and is required for its formation. Using siRNA‐mediated silencing, pharmacological inhibition, genetic knockout and stable overexpression, we elucidate key roles for Cdc42 Rho GTPase and guanine nucleotide exchange factor Vav in promoting actin polymerization at the lysosomal synapse, and we rule out roles for Rac1 and Rac2. These data indicate that dynamic actin rearrangement and polymerization via Vav and Cdc42 aids compartment formation, catabolism of agLDL and promotes foam cell formation.Support or Funding InformationThe project described was supported by National Institutes of Health grants R37‐DK27083 and R01‐HL093324. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. R.K.S. is an American Heart Association Stanley Stahl Postdoctoral Fellow (ID: 15POST22990022).This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
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