Prosaposin mediates inflammation in atherosclerosis

Area of Science:

• Immunology
• Metabolic pathways
• Cardiovascular disease research

Background:

• Macrophages are key players in atherosclerosis pathogenesis.
• Cellular metabolism, regulated by mechanistic target of rapamycin (mTOR) signaling, dictates macrophage inflammatory properties.

Purpose of the Study:

• To investigate the role of mTOR signaling and identify novel therapeutic targets in atherosclerosis.
• To explore the link between mTOR signaling and the lysosomal protein prosaposin (Psap).

Main Methods:

• Utilized myeloid cell-specific nanobiologics in apolipoprotein E-deficient (Apoe-/-) mice to target mTOR and S6K1 pathways.
• Analyzed transcriptome modifications to identify genes related to mTOR signaling.
• Conducted in vitro experiments and bone marrow transplantation studies in low-density lipoprotein receptor knockout (Ldlr-/-) mice.
• Examined PSAP expression in human carotid atherosclerotic plaques.

Main Results:

• Targeting mTOR/S6K1 pathways rapidly reduced inflammatory activity of plaque macrophages.
• Identified Psap as a gene closely related to mTOR signaling.
• Psap inhibition suppressed glycolysis and oxidative phosphorylation in vitro.
• Psap deficiency reduced atherosclerosis development and plaque inflammation in Ldlr-/- mice.
• Confirmed a correlation between PSAP expression and inflammation in human atherosclerotic plaques.

Conclusions:

• mTOR signaling is a critical regulator of macrophage metabolism and inflammation in atherosclerosis.
• Prosaposin (Psap) is mechanistically linked to mTOR signaling and macrophage bioenergetics.
• Psap represents a potential therapeutic target for reducing atherosclerosis and plaque inflammation.