Abstract 1206: Increased Oxidative Stress due to Dysfunctional HDL in Scavenger Receptor BI Knockout Mice
HDL reduces atherosclerosis by facilitating reverse cholesterol transport and by its anti-oxidant properties. In the current study the effect of disruption of SR-BI, a prominent regulator of HDL metabolism, on the activity of the HDL-associated anti-oxidant enzymes paraoxonase 1 (PON1) and platelet-activating factor acetylhydrolase (PAF-AH) as well as in vivo oxidative stress were investigated. SR-BI deficiency induces the accumulation of abnormally large HDL particles due to an impaired delivery of HDL cholesterol esters to the liver. Interestingly, despite the increased HDL levels, PAF-AH activity was significantly lower in SR-BI knockout (KO) mice (501±44 compared to 687±44 nmol/mL/min for wildtype (WT) mice, P<0.01). In addition, also the activity of PON1 was significantly reduced in absence of SR-BI. The paraoxonase activity of PON1 was 1.4-fold (P<0.01) lower in SR-BI KO mice as compared to WT controls, while the arylesterase activity of PON1 was 1.7-fold (P<0.001) lower. The effect of SR-BI deficiency on in vivo oxidative stress was evaluated by measuring isoprostane F2α-VI (iPF2α-VI) and protein carbonyls, two distinct markers for lipid and protein oxidation, respectively. Compared with WT animals, SR-BI KO mice had 1.4-fold higher levels of plasma iPF2α-VI (420±40 pg/mL vs 303±23, P<0.05), while urinary excretion was also increased (1.95±0.14 vs 0.98±0.08 ng/mg creatinine, P<0.0001). In addition, plasma and urinary carbonyls were higher in SR-BI KO than in WT animals (493±46 vs 357±28 pg/mL, P<0.01 and 1.8±0.4 vs 0.9±0.1 ng/mg, P<0.01, respectively). Furthermore, iPF2α-VI and carbonyl levels were 2.3-fold (P<0.001) and 1.3-fold (P<0.05), respectively higher in livers of SR-BI KO mice as compared to WT animals. In reaction to the increased oxidative stress the expression of several endogenous anti-oxidant systems, including GPx1 (1.7-fold; P<0.001), GPx4 (1.2-fold; P<0.05), SOD1 (1.2-fold; P<0.05), SOD2 (1.4-fold; P<0.05), and GSTA4 (1.8-fold; P<0.05) was upregulated in livers of SR-BI KO mice. In conclusion, SR-BI deficiency results in reduced activities of the anti-oxidant enzymes PON1 and PAF-AH and a significant increase in oxidative stress in vivo, potentially contributing to the pro-atherogenic effect of SR-BI deficiency.