Differential Trafficking of Oxidized LDL and Oxidized LDL Immune Complexes in Macrophages: Impact on Oxidative Stress

Oxidized low-density lipoproteins (oxLDL) and oxLDL-containing immune complexes (oxLDL-IC) contribute to formation of lipid-laden macrophages (foam cells). It has been shown that oxLDL-IC are considerably more efficient than oxLDL in induction of foam cell formation, inflammatory cytokines secretion, and cell survival promotion. Whereas oxLDL is taken up by several scavenger receptors, oxLDL-IC are predominantly internalized through the FCgamma receptor I (FCgamma RI). This study examined differences in intracellular trafficking of lipid and apolipoprotein moieties of oxLDL and oxLDL-IC and the impact on oxidative stress.Fluorescently labeled lipid and protein moieties of oxLDL co-localized within endosomal and lysosomal compartments in U937 human monocytic cells. In contrast, the lipid moiety of oxLDL-IC was detected in the endosomal compartment, whereas its apolipoprotein moiety advanced to the lysosomal compartment. Cells treated with oxLDL-IC prior to oxLDL demonstrated co-localization of internalized lipid moieties from both oxLDL and oxLDL-IC in the endosomal compartment. This sequential treatment likely inhibited oxLDL lipid moieties from trafficking to the lysosomal compartment. In RAW 264.7 macrophages, oxLDL-IC but not oxLDL induced GFP-tagged heat shock protein 70 (HSP70) and HSP70B', which co-localized with the lipid moiety of oxLDL-IC in the endosomal compartment. This suggests that HSP70 family members might prevent the degradation of the internalized lipid moiety of oxLDL-IC by delaying its advancement to the lysosome. The data also showed that mitochondrial membrane potential was decreased and generation of reactive oxygen and nitrogen species was increased in U937 cell treated with oxLDL compared to oxLDL-IC.Findings suggest that lipid and apolipoprotein moieties of oxLDL-IC traffic to separate cellular compartments, and that HSP70/70B' might sequester the lipid moiety of oxLDL-IC in the endosomal compartment. This mechanism could ultimately influence macrophage function and survival. Furthermore, oxLDL-IC might regulate the intracellular trafficking of free oxLDL possibly through the induction of HSP70/70B'

Parent-offspring and sibling conflict in Galapagos fur seals and sea lions

Trillmich F, Wolf JBW. Parent-offspring and sibling conflict in Galapagos fur seals and sea lions. BEHAVIORAL ECOLOGY AND SOCIOBIOLOGY. 2008;62(3):363-375.Parent-offspring conflict theory is well supported by theoretical arguments. However, empirical observations are often difficult to interpret and have contradicted one of its most appealing predictions that parent and offspring should disagree over killing of nest or littermates. We present the first examples of deadly conflict between siblings of different cohorts. In Galapagos fur seals (Arctocephalus galapagoensis) and sea lions (Zalophus wollebaeki), mothers often wean their single offspring at 2 years. This leads to a situation where up to 23% of all pups are born while the older sibling is still being nursed. Younger siblings are disadvantaged by being born lighter than neonates without older still dependent siblings. Pups born while an older sib is still dependent grow less in early life (fur seal) and suffer increased early mortality (both species) through direct aggression or scramble competition with the older sibling. This effect is much stronger in years of high sea surface temperature (El Nino) indicating low marine productivity and if the older offspring is a male. In both species, mothers interfere aggressively in this conflict by defending the younger offspring. In years of El Nino, intense resistance to maternal aggression by the older offspring happens frequently in the fur seal. Such resistance against weaning can induce maternal neglect of the newborn. Given substantial year to year variation in offspring growth, maternal aggression forces weaning in the older sibling only if it has reached sufficient size to support itself by foraging. In Galapagos fur seals, pups with older siblings can either represent insurance against loss of older offspring or extra reproductive value

Oxidized LDL: Diversity, Patterns of Recognition, and Pathophysiology

Oxidative modification of LDL is known to elicit an array of pro-atherogenic responses, but it is generally underappreciated that oxidized LDL (OxLDL) exists in multiple forms, characterized by different degrees of oxidation and different mixtures of bioactive components. The variable effects of OxLDL reported in the literature can be attributed in large part to the heterogeneous nature of the preparations employed. In this review, we first describe the various subclasses and molecular composition of OxLDL, including the variety of minimally modified LDL preparations. We then describe multiple receptors that recognize various species of OxLDL and discuss the mechanisms responsible for the recognition by specific receptors. Furthermore, we discuss the contentious issues such as the nature of OxLDL in vivo and the physiological oxidizing agents, whether oxidation of LDL is a prerequisite for atherogenesis, whether OxLDL is the major source of lipids in foam cells, whether in some cases it actually induces cholesterol depletion, and finally the Janus-like nature of OxLDL in having both pro- and anti-inflammatory effects. Lastly, we extend our review to discuss the role of LDL oxidation in diseases other than atherosclerosis, including diabetes mellitus, and several autoimmune diseases, such as lupus erythematosus, anti-phospholipid syndrome, and rheumatoid arthritis. Antioxid. Redox Signal. 13, 39–75