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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2007;27:2413.)
© 2007 American Heart Association, Inc.

Atherosclerosis and Lipoproteins

Increased Oxidative Stress in Scavenger Receptor BI Knockout Mice With Dysfunctional HDL

Miranda Van Eck; Menno Hoekstra; Reeni B. Hildebrand; Yuemang Yaong; Dominique Stengel; J. Kar Kruijt; Wolfgang Sattler; Uwe J.F. Tietge; Ewa Ninio; Theo J.C. Van Berkel; Domenico Praticò

From the Division of Biopharmaceutics (M.V.E., M.H., R.B.H., J.K.K., Th.J.C.V.B.), Leiden/Amsterdam Center for Drug Research, Leiden University, The Netherlands; INSERM UMRS525 (D.S., E.N.), Faculté de Médecine, Université Pierre et Marie Curie-Paris 6 and Faculté de Médecine Pierre et Marie Curie, Paris, France; Institute of Molecular Biology and Biochemistry (W.S.), Center for Molecular Medicine, Medical University of Graz, Austria; Center for Liver, Digestive, and Metabolic Disease (U.J.F.T.), University Medical Center Groningen, The Netherlands; and the Department of Pharmacology (D.P., Y.Y.), Temple University, Philadelphia, Pa.

Correspondence to M. Van Eck, LACDR, Division of Biopharmaceutics, Gorlaeus Laboratories, Einsteinweg 55, P.O. Box 9502 2300 RA Leiden, The Netherlands. E-mail m.eck{at}LACDR.LeidenUniv.nl

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 F2-VI (iPF2-VI) and protein carbonyls. Compared with wild-type animals, SR-BI knockouts had 1.4-fold (P<0.05) higher levels of plasma iPF2-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, iPF2-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.

HDL reduces atherosclerosis by its antioxidant properties. In the current study we show that disruption of SR-BI, a prominent regulator of HDL metabolism, decreases the activity of the HDL-associated antioxidant enzyme paraoxonase 1 and leads to increased oxidative stress, potentially contributing to the proatherogenic effect of SR-BI deficiency.

Key Words: HDL cholesterol • antioxidant enzymes • oxidative stress • isoprostanes • mouse models

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