on August 23, 2007
Published online before print August 23, 2007, doi: 10.1161/ATVBAHA.107.145474
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Submitted on July 12, 2006
Accepted on August 6, 2007
Increased Oxidative Stress in Scavenger Receptor BI Knockout Mice With Dysfunctional HDL
Miranda Van Eck *;
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.), Temple University, Philadelphia, Pa.
* To whom correspondence should be addressed. 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.
Key words: HDL cholesterol • antioxidant enzymes • oxidative stress • isoprostanes • mouse models
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