Differential regulation of acid sphingomyelinase in macrophages stimulated with oxidized low‐density lipoprotein (LDL) and oxidized LDL immune complexes: role in phagocytosis and cytokine release

Abstract

Summary Oxidized low‐density lipoprotein (oxLDL) and oxLDL‐containing immune complexes (oxLDL‐IC) contribute to the formation of lipid‐laden macrophages (foam cells). Fcγ receptors mediate uptake of oxLDL‐IC, whereas scavenger receptors internalize oxLDL. We have previously reported that oxLDL‐IC, but not free oxLDL, activate macrophages and prolong their survival. Sphingomyelin is a major constituent of cell membranes and lipoprotein particles and acid sphingomyelinase (ASMase) hydrolyses sphingomyelin to generate the bioactive lipid ceramide. ASMase exists in two forms: lysosomal (L‐ASMase) and secretory (S‐ASMase). In this study we examined whether oxLDL and oxLDL‐IC regulate ASMase differently, and whether ASMase mediates monocyte/macrophage activation and cytokine release. The oxLDL‐IC, but not oxLDL, induced early and consistent release of catalytically active S‐ASMase. The oxLDL‐IC also consistently stimulated L‐ASMase activity, whereas oxLDL induced a rapid transient increase in L‐ASMase activity before it steadily declined below baseline. Prolonged exposure to oxLDL increased L‐ASMase activity; however, activity remained significantly lower than that induced by oxLDL‐IC. Further studies were aimed at defining the function of the activated ASMase. In response to oxLDL‐IC, heat‐shock protein 70B’ (HSP70B’) was up‐regulated and localized with redistributed ASMase in the endosomal compartment outside the lysosome. Treatment with oxLDL‐IC induced the formation and release of HSP70‐containing and IL‐1β‐containing exosomes via an ASMase‐dependent mechanism. Taken together, the results suggest that oxLDL and oxLDL‐IC differentially regulate ASMase activity, and the pro‐inflammatory responses to oxLDL‐IC are mediated by prolonged activation of ASMase. These findings may contribute to increased understanding of mechanisms mediating macrophage involvement in atherosclerosis.

Immune complex formation in human diabetic retina enhances toxicity of oxidized LDL towards retinal capillary pericytes

“…It is now well-known that modifi cation of LDL may render it immunogenic, leading to the formation of LDL immune complexes (LDL-ICs) ( 19 ). Recently, in the Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications (DCCT/ EDIC) cohort, we found that increased levels of circulating ox-LDL-ICs predicted risk for severe nonproliferative DR (NPDR) and proliferative DR (PDR) in type 1 diabetes ( 20 ).…”

“…Others have shown that plasma levels of antibodies to malondialdehyde-modifi ed apolipoprotein B-100 are correlated with DR severity in type 2 diabetes ( 21 ). Further emphasizing the importance of ox-LDL-ICs, it is now established that in plasma, only a minor proportion of ox-LDL circulates free; 95% circulates in ICs ( 7,19 ). For ox-LDL-ICs, as with ox-LDL, changes observed in plasma may provide only an indirect index of events in tissue.…”

“…In plasma, ox-LDL represents only a small fraction of total LDL ( 7 ), and also, most ox-LDL is incorporated in ICs ( 19 ). In atheromatous plaque, ox-LDL concentration may be as much as 70-fold higher than in plasma ( 16 ).…”

Molecular Biology of Atherosclerosis

“…These oxLDL immune complexes are reported to promote greater foam cell formation, release of active secretory acid sphingomyelinase, prolonged activation of lysosomal acid sphingomyelinase, and release of more cytokines compared with oxLDL alone. Yet oxLDL-IgG complexes also promote greater macrophage survival with less ROS production, mediated by intracellular Fc␥RI signaling including Akt activation (36, 704,1811). The ultimate effect of oxLDL-IgG complexes on atherosclerosis remains unresolved, however.…”

The study on therapy effect of Danqi pill to renin-angiotensin-aldosterone system (RAAS) and lipid metabolism disorder in coronary heart disease

“…Studies also had shown that activation of RAAS system including the up-regulation of Ang II and Ald activated NOX4 through AT1 receptor pathway (Imanishi et al, 2005), and induced ROS by the electron transformation (Quinn and Gauss, 2004). ROS can modify LDL to be OX-LDL (Truman et al, 2012;Galle et al, 2003) and impaired endothelial function especially the NO content. What's more, ox-LDL is the critical risk factors of lipid metabolism disorder that can contribute to CHD (Koenig et al, 2011).…”