Retroviral gene therapy in ApoE-deficient mice - ApoE expression in the artery wall reduces early foam cell lesion formation

Background-Apolipoprotein E (apoE) has long been known to play an important role in the clearance of plasma lipoproteins, More recently, a direct role for apoE in delaying atherogenesis has been proposed. Macrophage productio n of apoE in the artery wall has been demonstrated to provide protection ag ainst atherosclerotic lesion development independently from its role in lip oprotein clearance. However, whether macrophage apoE can affect lesion grow th at all stages of atherogenesis remains to be established. Methods and Results-To evaluate the role of macrophage apoE in different st ages of atherogenesis, as well as to establish a novel gene therapy approac h to atherosclerotic vascular disease, we used an apoE-expressing retroviru s to transduce apoE-deficient (-/-) bone marrow for transplantation into ap oE(-/-) recipient mice. Three weeks after bone marrow transplantation, apoE was expressed from arterial macrophages and was detectable in plasma assoc iated with lipoproteins at 0.5% to 1% of normal levels but did not affect p lasma cholesterol levels. We used 2 groups of recipient mice: younger mice with lesions consisting primarily of foam cells and older mice with more ad vanced lesions. When either the mouse or human apoE transgenes were express ed in mice from 5 to 13 weeks of age, there was a significant reduction in lesion area, whereas no effects were detected in mice that expressed apoE f rom 10 to 26 weeks of age. Conclusions-We demonstrate that arterial macrophage apoE secretion can dela y atherogenesis if expressed during foam cell formation but is not benefici al during the later stages of atherogenesis, These data also provide eviden ce that apoE transgene expression from arterial macrophages may have therap eutic applications.