FIGURE 2.

Therapeutics for atherosclerosis targeting lysosomal dysfunction. Cyclodextrin (1) releases the FC sequestered inside lysosomes. ERT (2) is based on the delivery of recombinant LAL that is taken up by mannose-6-phosphate receptors (M6PR) and directed to the lysosomes. In the acidic lumen of lysosomes LAL is released from the M6PR and catalyzes the hydrolysis of accumulated CE. Cathepsin (CTS) inhibitors (3) may be beneficial to plaque stability by preventing the degradation of the ECM, and by decreasing the aggregation of LDL, which hampers its uptake by non-regulated SRs. Both mTOR inhibitors (4) and trehalose (5) drive lysosome biogenesis by stimulating the translocation of TFEB to the nucleus where it drives the transcription of lysosomal genes. SRT (6) is based on the inhibition of the (glucosylceramide) synthase responsible for the production of glycosphingolipids (GSLs) that would otherwise accumulate inside lysosomes. All these strategies, with the exception of (3), have the potential to decrease the accumulation of lysosomal substrates and thereby restore membrane integrity, preventing cathepsin release and NRLP3 inflammasome activation (IL-1β production and release). This has only been experimentally demonstrated in the case of trehalose treatment. Some images in this figure were adapted with permission from Servier Medical Art, licensed under a Creative Common Attribution 3.0 Generic License (http://smart.servier.com/).