Regression of Atherosclerosis Induced by Liver-Directed Gene Transfer of Apolipoprotein A-I in Mice

Abstract

Background-The ability of apolipoprotein (apo)A-I to induce regression of preexisting atherosclerotic lesions has not been determined, and a mouse model of atherosclerosis regression has not yet been reported. Methods and Results-LDL receptor-deficient mice were fed a western-type diet for 5 weeks to induce atherosclerotic lesions. A second-generation recombinant adenovirus encoding human apoA-I or a control adenovirus were injected intravenously in order to express apoA-I in the liver. Three days after injection, total apoA-I levels in mice injected with the apoA-I-expressing adenovirus were 216Ϯ16.0 mg/dL, compared with 68.0Ϯ3.0 mg/dL in control virus-injected mice (PϽ0.001). HDL cholesterol levels in mice injected with the AdhapoA-I vector 7 days after injection were 189Ϯ21.0 mg/dL, compared with 123Ϯ8.0 mg/dL in control virus-injected mice (PϽ0.02). Total and non-HDL cholesterol levels did not differ between the 2 groups. Atherosclerotic lesion area was quantified by en face analysis of the aorta and cross-sectional analysis of the aortic root. Compared with baseline mice, atherosclerosis progressed in mice injected with the control adenovirus. In contrast, in mice expressing apoA-I compared with baseline mice, total en face aortic lesion area was reduced by 70% and aortic root lesion was reduced by 46%. Expression of apoA-I was associated with a significant reduction in the fraction of lesions occupied by macrophages and macrophage-derived foam cells. Conclusions-Liver-directed gene transfer of human apoA-I resulted in significant regression of preexisting atherosclerotic lesions in LDL receptor-deficient mice as assessed by 2 independent methods. (Circulation. 1999;100:1816-1822.)

Long-Term Stable Expression of Human Apolipoprotein A-I Mediated by Helper-Dependent Adenovirus Gene Transfer Inhibits Atherosclerosis Progression and Remodels Atherosclerotic Plaques in a Mouse Model of Familial Hypercholesterolemia

“…Two studies published previously in Circulation studied the effect of transient apoA-I gene transfer on atherosclerosis development in various mouse models 23,24 and concluded that short-term hepatic apoA-I expression produced regression of aortic atherosclerosis. Benoit et al 23 used human apoA-I transgenic mice (with concomitant apoE deficiency) as a study model to obtain the longest possible transgene expression.…”

Does Therapeutic Intervention Achieve Slowing of Progression or Bona Fide Regression of Atherosclerotic Lesions?

“…40 In another model system, namely, LDL receptordeficient mice, liver-directed gene transfer of apoA-I was performed. 41 Plasma levels of human apoA-I peaked 7 days after injection and declined during the subsequent week. A remarkable regression of lesions in the aortic root was observed 4 weeks after the adenovirus injection.…”

“…In the treated mice, the percent lesion area occupied by macrophages and macrophage-derived foam cells was significantly reduced. 41 …”

Association of a Model Class A (Apolipoprotein) Amphipathic α Helical Peptide with Lipid

“…Epidemiological studies have established an inverse correlation between the plasma levels of high density lipoprotein (HDL) 4 cholesterol and the risk of coronary artery disease. In support of a protective role of human apolipoprotein A-I (apoA-I), the major protein accounting for 70% of the total protein present in HDL, it has been shown that expression of human apoA-I in atherosclerosis-sensitive mouse models leads to inhibition of atherosclerosis (1)(2)(3)(4). In addition, recently it has been shown that infusion of recombinant HDL particles consisting of apoA-I Milano regressed already existing lesions in humans (5).…”