Objective: In the current study the effect of disruption of SR-BI, a prominent regulator of HDL metabolism, on the activity of the HDL-associated antioxidant enzymes PON1 and PAF-AH as well as in vivo oxidative stress were investigated.
Methods and results: SR-BI deficiency resulted in 1.4-fold (P<0.001) and 1.6-fold (P<0.01) lower serum paraoxonase and arylesterase activity of PON1, respectively. Furthermore, a trend to slightly lower PAF-AH activity was observed. In vivo oxidative stress was evaluated by measuring isoprostane F2alpha-VI (iPF2alpha-VI) and protein carbonyls. Compared with wild-type animals, SR-BI knockouts had 1.4-fold (P<0.05) higher levels of plasma iPF2alpha-VI, whereas urinary excretion was increased 2-fold (P<0.0001). Plasma carbonyls were 1.5-fold (P<0.05) higher in SR-BI knockout animals. Furthermore, iPF2alpha-VI and carbonyl levels were 2.1-fold (P<0.01) and 1.4-fold (P<0.01), respectively, increased in livers of SR-BI knockout mice, and in reaction to the increased oxidative stress the expression of several endogenous antioxidant systems was upregulated. On challenging the SR-BI knockout mice with an atherogenic Western-type diet, a further increase in oxidative stress in these animals was observed.
Conclusion: SR-BI deficiency results in a reduced activity of the antioxidant enzyme PON1 and a significant increase in oxidative stress, potentially contributing to the proatherogenic effect of SR-BI deficiency.