Title : Normalizing effects of bacterial serum opacity factor on plasma lipids, tissues, and atherosclerosis
Abstract:
Although plasma HDL-C levels negatively correlate with atherosclerotic cardiovascular disease (ACVD), attempts to reduce ACVD risk by raising plasma HDL have disappointed. Thus, hypotheses about salutary HDL effects have shifted from higher-is-better to function-is-more-important. The SRB1-/- mouse is an extreme model of HDL dsyfunctionality; compared to WT mice, SRB1-/- mice have higher plasma HDL levels and an HDL surface that is free cholesterol (FC)-rich (60 vs. 15 mol%). Superposition of high plasma HDL levels and a high mol% FC in SRB1-/- mice is expected to increase HDL-FC bioavailablity that contributes to whole-body FC-toxicity and the observed metabolic abnormalities—impaired red blood cells and platelets and increased atherosusceptibility, despite having high plasma HDL-C levels; moreover, female SRB1-/- mice are infertile. Dietary probucol, an HDL-lowering drug, partially reverses infertility in SR-B1-/- mice. The mechanisms underlying ovaritoxicity are unknown and interventions that fully reverse this state have not been identified. We have previously shown that bacterial protein, serum opacity factor (SOF), which acts on HDL and lowers cholesterol in WT mice by ~43% in 3 hours, normalized HDL and rescued infertility in SRBI -/- female mice. SOF catalyzes the disproportionation of HDL into three products: a cholesteryl ester-rich micro emulsion (CERM) with abundant apo E, small neo-HDL, and lipid-free apo AI. Decrease in plasma cholesterol in SOF treated mice is attributed to diverting the CERM particle to hepatic LDL Receptor. We hypothesized that SOF treatment in SRBI1-/- mice would also rescue the dysfunctional phenotype in erythrocytes and lead to atheroprevention in high-fat fed mice. AAVSOF was used to constitutively express SOF in mice for these studies. Erythrocytes from SRBI-/- mice treated with SOF had significantly fewer reticulocytes and abnormal cells compared to non-treated mice. There was no significant difference in the total average plaque area of the treated mice vs. controls. However, when grouped by gender, males had less plaque burden than female mice in the atheroprevention study.
