title: 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.
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.
authors.affiliation: Center for Molecular and Vascular Biology, University of Leuven, Leuven, Belgium.
authors.forename: B
authors.initials: B
authors.lastname: De Geest
authors.forename: D
authors.initials: D
authors.lastname: Stengel
authors.forename: M
authors.initials: M
authors.lastname: Landeloos
authors.forename: M
authors.initials: M
authors.lastname: Lox
authors.forename: L
authors.initials: L
authors.lastname: Le Gat
authors.forename: D
authors.initials: D
authors.lastname: Collen
authors.forename: P
authors.initials: P
authors.lastname: Holvoet
authors.forename: E
authors.initials: E
authors.lastname: Ninio
mesh_terms: D043203:1-Alkyl-2-acetylglycerophosphocholine Esterase; D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D000975:Antioxidants / Q000378:metabolism; D016632:Apolipoprotein A-I / Q000096:biosynthesis / Q000097:blood / Q000235:genetics*; D001057:Apolipoproteins E / Q000172:deficiency*; D043303:Aryldialkylphosphatase; D001797:Blood Protein Electrophoresis; D008076:Cholesterol, HDL / Q000097:blood; D002850:Chromatography, Gel; D003176:Complement C3 / Q000032:analysis; D016207:Cytokines / Q000097:blood; D004950:Esterases / Q000235:genetics / Q000378:metabolism; D005260:Female; D005786:Gene Expression Regulation; D018014:Gene Transfer Techniques; D006801:Humans; D008075:Lipoproteins, HDL / Q000097:blood* / Q000737:chemistry; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D010741:Phospholipases A / Q000235:genetics / Q000378:metabolism; D010972:Platelet Activating Factor / Q000378:metabolism; D012709:Serum Albumin / Q000032:analysis; D013997:Time Factors; D015854:Up-Regulation; D000511:alpha-Macroglobulins / Q000032:analysis
chemical_list: D000975:Antioxidants; D016632:Apolipoprotein A-I; D001057:Apolipoproteins E; D008076:Cholesterol, HDL; D003176:Complement C3; D016207:Cytokines; D008075:Lipoproteins, HDL; D010972:Platelet Activating Factor; D012709:Serum Albumin; D000511:alpha-Macroglobulins; D004950:Esterases; D010741:Phospholipases A; D043203:1-Alkyl-2-acetylglycerophosphocholine Esterase; D043303:Aryldialkylphosphatase; C468406:PON1 protein, human