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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2000;20:e68.)
© 2000 American Heart Association, Inc.

Atherosclerosis and Lipoproteins

Effect of Overexpression of Human Apo A-I in C57BL/6 and C57BL/6 Apo E–Deficient Mice on 2 Lipoprotein-Associated Enzymes, Platelet-Activating Factor Acetylhydrolase and Paraoxonase

Comparison of Adenovirus-Mediated Human Apo A-I Gene Transfer and Human Apo A-I Transgenesis

Bart De Geest; Dominique Stengel; Michèle Landeloos; Marleen Lox; Laurence Le Gat; Désiré Collen; Paul Holvoet; Ewa Ninio

From the Center for Molecular and Vascular Biology (B.D.G., M.L, M.L, D.C., P.H.), University of Leuven, Leuven, Belgium; and INSERM U321 (D.S., L.L.G., E.N.), Lipoproteins and Atherogenesis, Institut Fédératif Muscle Coeur et Vaisseaux, Hôpital Pitié-Salpêtrière and UFR Médecine Sud (Université Pierre et Marie Curie), Paris, France.

Correspondence to Paul Holvoet, PhD, Center for Molecular and Vascular Biology, Campus Gasthuisberg, Herestraat 49, 3000 Leuven, Belgium. E-mail paul.holvoet{at}med.kuleuven.ac.be

Abstract—Various mechanisms may contribute to the antiatherogenic potential of apolipoprotein A-I (apo A-I) and high density lipoproteins (HDLs). Therefore, the effect of adenovirus-mediated human apo A-I gene transfer or human apo A-I transgenesis on platelet-activating factor acetylhydrolase (PAF-AH) and arylesterase/paraoxonase (PON1) was studied in C57BL/6 and C57BL/6 apo E^-/- mice. Human apo A-I transgenesis in C57BL/6 mice resulted in a 4.2-fold (P<0.0001) increase of PAF-AH and a 1.7-fold (P=0.0012) increase of PON1 activity. The apo E deficiency was associated with a 1.6-fold (P=0.008) lower PAF-AH and a 2.0-fold (P=0.012) lower PON1 activity. Human apo A-I transgenesis in C57BL/6 apo E^-/-mice increased PAF-AH and PON1 activity by 2.1-fold (P=0.01) and 2.5-fold (P=0.029), respectively. After adenovirus-mediated gene transfer of human apo A-I into C57BL/6 apo E^-/-mice, a strong correlation between human apo A-I plasma levels and PAF-AH activity was observed at day 6 (r=0.92, P<0.0001). However, PON1 activity failed to increase, probably as a result of cytokine-mediated inhibition of PON 1 expression. In conclusion, this study indicates that overexpression of human apo A-I increases HDL-associated PAF-AH activity. PON1 activity was also increased in human apo A-I transgenic mice, but not after human apo A-I gene transfer, a result that was probably related to cytokine production induced in the liver by the adenoviral vectors. Increased levels of these HDL-associated enzymes may contribute to the anti-inflammatory and antioxidative potential of HDL and thereby to the protection conferred by HDL against atherothrombosis.

Key Words: HDL • gene transfer • platelet-activating factor acetylhydrolase • paraoxonase

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