Altered lipidome and antioxidative activity of small, dense HDL in normolipidemic rheumatoid arthritis: Relevance of inflammation

Abstract

Objective: High-density lipoprotein (HDL) particles exert potent antiatherogenic activities, including antioxidative actions, which are relevant to attenuation of atherosclerosis progression. Such activities are enriched in small, dense HDL and can be compromised under conditions of chronic inflammation like rheumatoid arthritis (RA). However, structure–function relationships of HDL largely remain indeterminate. Methods: The relationships between HDL structure and function were evaluated in normolipidemic patients with active RA (DAS28 > 3.2; n = 12) and in normolipidemic age-matched controls (n = 10). Small, dense HDL3b and 3c particles were isolated from plasma or serum by density gradient ultracentrifugation and their physicochemical characteristics, lipidome (by LC/MS/MS) and antioxidative function (as protection of normolipidemic LDL from free radical-induced oxidation) were evaluated. Results: As expected, active RA patients featured significantly elevated plasma levels of high-sensitivity C-reactive protein (hsCRP; p < 0.001) and serum amyloid A (SAA; p < 0.01) relative to controls. Antioxidative activity and weight % chemical composition of small, dense HDL did not differ between RA patients and controls (p > 0.05), whereas HDL phosphosphingolipidome was significantly altered in RA. Subgroup analyses revealed that RA patients featuring high levels of inflammation (hsCRP>10 mg/l) possessed small, dense HDL with reduced antioxidative activities (p < 0.01). Furthermore, antioxidative activity of HDL was inversely correlated with plasma hsCRP (p < 0.01). Conclusions: These data revealed that (i) despite normolipidemic state, the lipidome of small, dense HDL was altered in RA and (ii) high levels of inflammation can be responsible for the functional deficiency of small, dense HDL in RA.