Abstract 431: Lipoprotein Metabolism and Transendothelial Apolipoprotein A-I Transport in Mice With an Endothelium-Specific Knockout of ATP Binding Cassette Transporter A1

Abstract

Low plasma levels of high density lipoprotein (HDL) cholesterol as well as apolipoprotein A-I (ApoA-I) are associated with increased risk of coronary heart disease. HDL and ApoA-I exert multiple potentially anti-atherogenic activities. Several of them the including stimulation of cholesterol efflux from macrophage foam cells for reverse cholesterol transport are exerted in the vascular wall rather than in the plasma compartment. HDL or apoA-I must hence pass the endothelium to enter and leave the arterial wall. We previously demonstrated in vitro that the transendothelial transport of ApoA-I involves the interaction with the ATP-binding cassette transporter (ABC) A1. To investigate the physiological relevance of transendothelial ApoA-I transport and its regulation by ABCA1, we generated an endothelium-specific ABCA1 knock-out mouse model (ABCA1e-/-) by expressing the Cre recombinase under the control of the Ve Cadherin gene in floxed ABCA1 -/- mice. Under both chow diet and a high fat/high cholesterol diet for 16 weeks the ABCA1e-/- mice did not differ from wild type mice by plasma levels of cholesterol or triglycerides or lipoprotein profiles. After injection of radio-iodinated ApoA-I, we found no difference in the decay of plasma radioactivity and the accumulation of radiolabel in different organs except the aorta. Compared to the aortas of wild type mice, aortas of ABCA1e-/- mice showed a significantly reduced enrichment of the radiolabel. Aortas of ABCA1e-/- mice also showed a slightly decreased enrichment of radiolabeled HDL but no difference in the enrichment of radiolabeled LDL or albumin. An ApoA-I mutant with defective ABCA1 interaction showed enhanced catabolism in both wild type and ABCA1e-/- mice as compared to wild type apoA-I. However the ABCA1-defective ApoA-I mutant did not accumulate differently in the aortas of wild type and ABCA1e-/- mice. Taken together the data support our concept and provide first in vivo evidence that transendothelial ApoA-I transport is a specific process modulated by ABCA1.