Research ArticleAtherosclerosis

Prosaposin mediates inflammation in atherosclerosis

See allHide authors and affiliations

Science Translational Medicine  10 Mar 2021:
Vol. 13, Issue 584, eabe1433
DOI: 10.1126/scitranslmed.abe1433

You are currently viewing the abstract.

View Full Text

Log in to view the full text

Log in through your institution

Log in through your institution

I-mTOR-rupting plaque inflammation

Atherosclerotic plaque progression is mediated by macrophages. Van Leent et al. studied the role of mechanistic target of rapamycin (mTOR) in macrophage metabolism in atherosclerosis. In mouse models of atherosclerosis, nanobiologics inhibiting mTOR or one of its target proteins reduced plaque inflammation and down-regulated prosaposin, a gene involved in macrophage metabolism. Plaque samples from patients also contained prosaposin-expressing macrophages, demonstrating the translational potential of targeting mTOR signaling and altering macrophage metabolism for atherosclerosis.

Abstract

Macrophages play a central role in the pathogenesis of atherosclerosis. The inflammatory properties of these cells are dictated by their metabolism, of which the mechanistic target of rapamycin (mTOR) signaling pathway is a key regulator. Using myeloid cell–specific nanobiologics in apolipoprotein E–deficient (Apoe−/−) mice, we found that targeting the mTOR and ribosomal protein S6 kinase-1 (S6K1) signaling pathways rapidly diminished plaque macrophages’ inflammatory activity. By investigating transcriptome modifications, we identified Psap, a gene encoding the lysosomal protein prosaposin, as closely related with mTOR signaling. Subsequent in vitro experiments revealed that Psap inhibition suppressed both glycolysis and oxidative phosphorylation. Transplantation of Psap−/− bone marrow to low-density lipoprotein receptor knockout (Ldlr−/−) mice led to a reduction in atherosclerosis development and plaque inflammation. Last, we confirmed the relationship between PSAP expression and inflammation in human carotid atherosclerotic plaques. Our findings provide mechanistic insights into the development of atherosclerosis and identify prosaposin as a potential therapeutic target.

View Full Text

Stay Connected to Science Translational Medicine