Apolipoprotein A-I stimulates secretion of apolipoprotein E by foam cell macrophages

Apolipoprotein A-I (apoA-I) overexpression inhibits atherogenesis in mice, and apolipoprotein E (apoE) secreted by foam cell macrophages may exert ant iatherogenic effects within the arterial wall. We hypothesized that interac tion between apoA-I and apoE contributed to the antiatherogenic properties of apoA-I, and therefore investigated whether apoA-I stimulated secretion o f apoE by foam cell macrophages, Cholesterol enrichment of primary murine a nd human macrophages increased spontaneous apoE secretion 2-fold, as quanti fied by Western blot and chemiluminescence detection. Human apoA-I caused a further marked increase of apoE secretion from both murine (3.8-fold, p < 0.01) and human (3.2-fold, p = 0.01) foam cells in a time- and concentratio n- dependent manner, and this increase was confirmed by immunoprecipitation of [S-35]methionine-labeled macrophage apoE, The protein synthesis inhibit or cycloheximide, but not the transcription inhibitor actinomycin D, marked ly inhibited apoE secretion to apoA-I (73.1 +/- 9.8% inhibition at 4 h) and completely suppressed apoE secretion beyond 4 h, Pretreatment of macrophag es with Pronase inhibited initial apoA-I-mediated apoE secretion by 70.5 +/ - 6.5% at 2 h, but by 8 h apoA-I-induced apoE secretion was the same in Pro nase-pretreated and non-pretreated cells. Non-apolipoprotein-mediated chole sterol efflux induced by trimethyl-beta cyclodextrin did not enhance apoE s ecretion, whereas phospholipid vesicles inducing the same degree of cholest erol efflux substantially enhanced apoE secretion, and apoA-I and phospholi pid vesicles in combination demonstrated additive induction of apoE secreti on. We conclude that apoA-I concurrently stimulates apoE secretion and chol esterol efflux from foam cell macrophages and that lipoprotein-derived apoA -I may enhance local secretion and accumulation of apoE in atherosclerotic lesions.