Intravenous Injection of Rabbit Apolipoprotein A-I Inhibits the Progression of Atherosclerosis in Cholesterol-Fed Rabbits

Abstract

The effects of intravenous injection of purified rabbit apoA-I on the progression of aortic atherosclerosis in cholesterol-fed rabbits were examined. In experiment 1, 28 rabbits were equally divided into groups A and B and fed a 0.5% cholesterol diet for 90 days. For the last 30 days, group B received 40 mg apoA-I every week. The fatty streak lesions in group B (23.9 +/- 15.6%) were significantly suppressed compared with those in group A (46.0 +/- 24.9%) (P < .05). In experiment 2, 33 rabbits were divided into four groups (8 or 9 rabbits per group) and fed a 0.5% cholesterol diet. Group A was killed on day 105, while groups B, C, and D were maintained for an additional 60 days on a normal diet, during which time groups C and D received 1 mg apoA-I every other day or 40 mg apoA-I every week, respectively. The lesions in group C (70.2 +/- 15.4%) and group D (65.7 +/- 20.0%) were significantly suppressed compared with those in group B (86.2 +/- 13.7%) (P < .05) but were not reduced to the level of group A (50.0 +/- 22.9%). Although apparent regression was not observed under these conditions, the present study provided the first evidence for the antiatherogenic effect of homologous and apoA-I on the progression of atherosclerosis in cholesterol-fed rabbits.

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

“…In the shorter experiment, 5 predominantly fatty streaks were induced, which can regress more easily (vide infra). In the longer experiment, 6 there was apparently a reduction in cholesterol content (ie, fatty streaks), but the more complex lesions did not regress. Repeated injections of phospholipid vesicles to cholesterol-fed rabbits resulted in significant cholesterol mobilization and regression of aortic intermediate lesions.…”

“…4 Badimon et al 5 fed rabbits a cholesterol-rich diet for 60 days, injected an HDL-VHDL fraction (weekly) during an additional 30 days on the same diet, and reported significant regression of lesions. In a later study, 6 rabbits fed cholesterol for 105 days were returned to the normal diet for 60 additional days, during which they were injected weekly with apoA-I, the major apolipoprotein of HDL. The treatment resulted in lesser cholesterol and CE accumulation compared with nontreated control animals, but regression was not achieved.…”

ApoA1 Reduces Free Cholesterol Accumulation in Atherosclerotic Lesions of ApoE–Deficient Mice Transplanted With ApoE–Expressing Macrophages

“…Injection of either purified apoA1 or HDL into cholesterol-fed rabbits inhibits the formation of fatty streak lesions. [31][32][33] When high levels of human apoA1 are expressed in transgenic mice, there is significant inhibition of fatty streak lesion formation, 34 and the overexpression of human apoA1 in apoE-deficient mice results in a dramatic reduction in atherosclerosis. 35,36 Similarly, atherosclerosis is reduced in cholesterol-fed transgenic rabbits that express human apoA1, 37 and a deficiency of apoA1 can exacerbate atherosclerosis in human apoB-transgenic mice.…”

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

“…Weekly intravenous injection of purified rabbit apoA-I reduced the progression of atherosclerosis in cholesterol-fed rabbits (despite no change in HDL cholesterol levels). 10 Transgenic overexpression of human apoA-I in hyperlipidemic Watanabe heritable hyperlipidemic rabbits delayed the development of atherosclerosis. 11 Overexpression of human apoA-I in transgenic mice reduced atherogenesis in C57BL/6 mice fed a high-fat diet, 12 in apoE-deficient mice, 13,14 and in human apo(a)-transgenic mice.…”