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 factoracetylhydrolase and paraoxonase - Comparison of adenovirus-mediated human apo A-I gene transfer and human apo A-I transgenesis

Various mechanisms may contribute to the antiatherogenic potential of apoli poprotein A-I (apo A-I) and high density lipoproteins (HDLs). Therefore, th e effect of adenovirus-mediated human apo A-I gene transfer or human apo A- I transgenesis on platelet-activating factor acetylhydrolase (PAF-AH) and a rylesterase/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 activ ity. The apo E deficiency was associated with a 1.6-fold (P=0.008) lower PA F-AH and a 2.0-fold (P=0.012) lower PON1 activity, Human apo A-I transgenes is 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 apa A-I plasma levels and PAF-AH activity was observed at da y 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 conclu sion, this study indicates that overexpression of human apo A-I increases H DL-associated PAF-AH activity. PON1 activity was also increased in human ap o 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 th e 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.