Rapid regression of atherosclerosis induced by liver-directed gene transfer of ApoE in ApoE-deficient mice

Apolipoprotein E (apoE) is a multifunctional protein synthesized by the liv er and tissue macrophages. ApoE-deficient mice have severe hyperlipidemia a nd develop accelerated atherosclerosis on a chow diet. Both liver-derived a nd macrophage-derived apoEs have been shown to reduce plasma lipoprotein le vels and slow the progression of atherosclerosis in apoE-deficient mice, bu t regression of atherosclerosis has not been demonstrated in this model. We utilized second-generation adenoviruses to achieve hepatic expression of h uman apoE in chow-fed, apoE-deficient mice with established atherosclerotic lesions of different stages. As expected, hepatic expression of human apoE 3 significantly reduced plasma cholesterol levels. Liver-derived apoE also accumulated substantially within preexisting atherosclerotic lesions, indic ating that plasma apoE gained access to the arterial intima, Hepatic expres sion of human apoE3 for 6 weeks resulted in significant quantitative regres sion of both early fatty streak lesions as well as advanced, complex lesion s in both the aortic root and the aortic arch. In addition, hepatic express ion of apoE induced substantial morphological changes in lesions, including decreased foam cells and increased smooth muscle cells and extracellular m atrix content. In parallel, human apoE4 and apoE2 were also expressed in th e liver by using recombinant adenoviruses. ApoE4 reduced cholesterol levels to the same extent as did apoE3 and also prevented progression but did not induce significant regression of preexisting lesions. ApoE2 reduced choles terol levels to a lesser degree than did apoE3 and apoE4 and lesion progres sion was reduced, but regression was not induced. In summary, (1) regressio n of preexisting atherosclerotic lesions in apoE-deficient mice can be rapi dly induced by hepatic expression of apoE, despite the absence of macrophag e-derived apoE; (2) the morphological changes seen in this model of regress ion resemble those in other animal models, induced over longer periods of t ime; (3) liver-derived apoE gained access to and was retained by intimal at herosclerotic lesions; and (4) apoE4 was less effective in inducing regress ion, despite its effects on plasma lipoproteins that were similar to those of apoE3. The rapid regression of preexisiting atherosclerotic lesions indu ced by apoE gene transfer in apoE-deficient mice could provide a convenient murine model for investigation of the molecular events associated with ath erosclerosis regression.