Macrophage-specific expression of human apolipoprotein E reduces atherosclerosis in hypercholesterolemic apolipoprotein E-null mice.

Abstract

apoE deficiency causes hyperlipidemia and premature atherosclerosis. To determine if macrophage-specific expression of apoE would decrease the extent of atherosclerosis, we expressed human apoE in macrophages of apoE-null mice (apoE-'-) and assessed the effect on lipid accumulation in cells of the arterial wall. Macrophage-specific expression of human apoE in normal mice was obtained by use of the visna virus LTR. These animals were bred with apoE-'-mice to produce animals hemizygous for expression of human apoE in macrophages in the absence of murine apoE (apoE -'-,hTgE '°). Low levels of human apoE mRNA were present in liver and spleen and high levels in lung and peritoneal macrophages. Human apoE was secreted by peritoneal macrophages and was detected in Kupffer cells of the liver. Human apoE in the plasma of apoE-'-,hTgE+'°mice (n = 30) was inversely correlated (P < 0.005) with the plasma cholesterol concentration. After 15 wk on a normal chow diet, atherosclerosis was assessed in apoE-'-,hTgE+'°ani-mals and in apoE-'-,hTgE°'°littermates matched for plasma cholesterol level (-450 mg/dl) and lipoprotein profile. There was significantly less atherosclerosis in both the aortic sinus and in the proximal aorta (P < 0.0001) in the animals expressing the human apoE transgene. In apo-E-'-,hTgE+10 animals, which had detectable atherosclerotic lesions, human apoE was detected in the secretory apparatus of macrophage-derived foam cells in the arterial wall. The data demonstrate that expression of apoE by macrophages is antiatherogenic even in the presence of high levels of atherogenic lipoproteins. The data suggest that apoE prevents atherosclerosis by promoting cholesterol efflux from cells of the arterial wall. (J. Clin. Invest. 1995. 96:2170-2179

A novel endothelial cell-based gene therapy platform for the in vivo delivery of apolipoprotein E

“…34,35 ApoE expressing macrophages or blood cells appeared to correct the metabolic defect, and to inhibit the atherosclerotic symptoms in these animals. In an alternative gene therapy approach, apoE deficiency was successfully corrected utilizing recombinant adenovirus vectors expressing human apoE.…”

“…[34][35][36][38][39][40] Although adenovirus-based gene transfer strategies are powerful, they raise major safety concerns when envisioned for treating long-term human diseases such as atherosclerosis. 37 Also, gene expression from these vectors is only transient and strong immunological responses increase the risk of further injections.…”

“…Alternatively, bone marrow transplantation after irradiation has also been used for gene delivery of apoE, however, this method has high morbidity and mortality associated with it. 34,35,40 Transformed cell lines such as BHK expressing the apoE gene may be tumorigenic and fibroblastic lines such as NIH/3T3 cells may have only a limited life-span.…”

ApoE genotype, cardiovascular risk and responsiveness to dietary fat manipulation

“…Monocyte-derived macrophages can produce up to 20% of the total apoE (Basu et al 1981(Basu et al , 1982Newman et al 1985;Wang-Iverson et al 1985). The anti-atherogenic roles of macrophage apoE have been demonstrated in apoE-null rodents (Bellosta et al 1995;Thorngate et al 2000). In these animals low-level tissue-specific expression of human apoE in macrophages inhibits atherogenesis without substantially influencing the plasma lipid profile.…”

Association of low-density lipoprotein receptor polymorphisms and outcome of hepatitis C infection

“…Lipoproteins may be involved in the redistribution of nutrients, neutralisation, binding or lysis of viruses and the binding of endotoxins and other biological agents. 44 Indeed, it has been shown that high lipoprotein levels reduce cytokine responses, 45 increase macrophage chemotaxis 46 and impair antiviral T cell immunity in hypercholcholesterolemic LDLR deficient mice. 47 It is hence plausible that genetic variation in the LDLR gene could affect the immune responses in HCV infection.…”