Targeting sortilin in immune cells reduces proinflammatory cytokines and atherosclerosis

Sortilin mediates vascular calcification via its recruitment into extracellular vesicles

“…The present study's results obtained from BM transplantation experiments suggest a role of sortilin on vascular calcification that is independent of immune cell-derived sortilin and therefore possibly mediated by SMC-derived sortilin. While current data show that sortilin affects hepatic lipoprotein secretion (9,15,16), emerging evidence suggests that sortilin contributes to cardiovascular disease development independently of circulating cholesterol (11,17), thus supporting our data that show no changes in cholesterol levels associated with sortilin deficiency in vascular calcification in mice.…”

“…For example, although one particular SNP decreased sortilin levels in the liver (9), sortilin levels in vascular tissue did not correlate with this SNP (11). The final evidence for the causal tripartite association among genetic variations of the sortilin locus, changes in vascular sortilin expression, and ectopic calcification macrophages, thus promoting atherosclerotic lesion formation (17). The present study's results obtained from BM transplantation experiments suggest a role of sortilin on vascular calcification that is independent of immune cell-derived sortilin and therefore possibly mediated by SMC-derived sortilin.…”

“…In addition to its protein-sorting functions in the brain (14), sortilin regulates lipid metabolism and inflammation. The global deletion of sortilin reduces secretion of very low-density lipoprotein (VLDL) from the liver (15,16) and reduces atherosclerosis in mice (17,18).…”

Ciliary neurotrophic factor (CNTF): New facets of an old molecule for treating neurodegenerative and metabolic syndrome pathologies

“…Sortilin forms with p75 NTR a pro-neurotrophin receptor mediating pro-neurotrophin-induced neuronal apoptosis during development [31][32][33]. Sortilin also modulates the immune response, participating in B cell survival regulation, pro-nerve growth factor-induced natural killer cell death as well as IFNg and IL6 secretion [34][35][36][37]. Therefore, immunomodulatory and survival effects of CNTF could be mediated through the binding of sortilin.…”

Protein sorting gone wrong – VPS10P domain receptors in cardiovascular and metabolic diseases

“…In support of the complex actions of this receptor in cardiovascular processes, new studies highlight the potential of sortilin to promote atherosclerotic processes in the vessel wall independent of its action in hepatic lipoprotein metabolism. Thus, deficiency of sortilin in the hematopoetic system attenuates atherosclerosis in mice, a mechanism attributed to the ability of this receptor to control release of pro-inflammatory cytokines from lymphocytes 45,46 and/or facilitate macrophage uptake of LDL and foam cell formation 47 .…”