POS0596 SERUM CHOLESTEROL LOADING CAPACITY ON MACROPHAGES IS LINKED TO OXIDIZED LOW-DENSITY LIPOPROTEIN AND REGULATED BY SEROPOSITIVITY AND C-REACTIVE PROTEIN IN PATIENTS WITH RHEUMATOID ARTHRITIS

Abstract

BackgroundExcessive cholesterol accumulation in macrophages underlies foam cell formation, initiation and progression of atherosclerosis. LDL oxidation and unregulated uptake of oxidized LDL by macrophages are critical in foam cell development. Cholesterol loading capacity (CLC) is the ability of serum to deliver cholesterol to cells and is related to foam cell formation. Rheumatoid arthritis (RA) serum increased cholesterol content in macrophages and promoted foam cell formation significantly more than control serum1. Although inflammation, LDL oxidation and antibodies to oxidized LDL (anti-oxLDL) may be higher in RA, their relationships and their individual and synergistic contributions to CLC in RA are unknown.ObjectivesTo explore determinants and moderators of serum CLC in patients with RA. We also investigated whether oxidized LDL influences CLC directly or indirectly through anti-oxLDL IgG and proprotein convertase subtilisin/Kexin type-9 (PCSK9), independently or conditionally on RA-related autoantibodies such as rheumatoid factor (RF) and anti-citrullinated protein antibodies (ACPA) or level of inflammation.MethodsIn an observational study of 104 patients, CLC was measured fluorimetrically as intracellular cholesterol content in human THP-1-derived macrophages after incubation with patient serum. Oxidized LDL was measured as oxidized phospholipids on apoB100 particles (oxPL-apoB100). Anti-oxLDL, PCSK9 and C-reactive protein (CRP) were also quantified. Associations of oxPL-apoB100, anti-oxLDL IgG and PCSK9 with CLC were examined with multivariable linear regression. A two-stage dual moderated mediation model explored whether an indirect association of oxPL-apoB100 with CLC through parallel mediators anti-oxLDL IgG and PCSK9 varied as a function of moderators CRP and RF/ACPA positivity.ResultsOxPL-apoB100, anti-oxLDL IgG and PCSK9 positively associated with CLC (all adjusted p<0.020). In the final dual moderated mediation model oxPL-apoB100 was directly linked to CLC only in dual seropositive patients (unstandardized b [95% bootstrap confidence interval]=2.08 [0.38-3.79], Figure 1). An indirect effect of oxPL-apoB100 on CLC through anti-oxLDL IgG was present and increased along with level of CRP (index of moderated mediation=0.55 [0.05-1.17]). CRP also moderated the other indirect effect of oxPL-apoB100 on CLC through PCSK9, but only in dual seropositive patients (conditional indirect effect=0.64 [0.13-1.30]).ConclusionOxidized LDL can directly influence CLC in dual seropositive RA patients, regardless of CRP. This suggests that targeting LDL oxidation in addition to inflammation may enable a more comprehensive reduction of atherosclerotic risk in these patients. Depending on CRP level, oxidized LDL also affected CLC indirectly via anti-oxLDL IgG and via PCSK9 in dual seropositive patients. If externally validated, our findings may have clinical implications for cardiovascular risk stratification and prevention.