Thus, the genetic polymorphism of apolipoprotein E may contribute to the individual risk of accelerated atherosclerosis in patients under maintenance hemodialysis.
In addition to the three major isoforms of apolipoprotein E (apo E-4, E-3, and E-2) and the new one (apo E-5) which was recently found in this laboratory, we have discovered an additional series of components, which showed themselves as at least three bands on an isoelectric focusing gel in the region of E-VII through E-V, in four patients with hyperlipidemia and atherosclerosis.
Patients affected by mixed hyperlipidemia should be investigated for their apolipoprotein E polymorphism because of the possible linkage of apolipoprotein E2/2 homozygosity, hyperlipidemia, and atherosclerosis.
Thus, apoE expression for 4 wk was sufficient to markedly reduce atherosclerosis, demonstrating the feasibility of gene therapy for correction of genetic hyperlipidemias resulting in atherosclerosis.
At present, 14 apoE variants have been found to be associated with familial dysbetalipoproteinemia, a genetic lipid disorder characterized by elevated plasma cholesterol and triglyceride levels and an increased risk for atherosclerosis.
Transgenic mice overexpressing human APOE*3Leiden are highly susceptible to diet-induced hyperlipoproteinemia and atherosclerosis due to a defect in hepatic uptake of remnant lipoproteins.
We investigated the association of apoE with carotid artery wall thickening (an index of atherosclerosis) in individuals with and without coronary artery disease (CAD).
Clinical and autoptical studies have suggested a predisposing role of the allele E4 of apolipoprotein E (apoE) in the development of atherosclerosis and cardiovascular disease.
However, unlike normal nontransgenic controls, in ApoE4 transgenic mice high density lipoprotein (HDL)-cholesterol levels remained high after high-fat feeding, which probably protected the animals from the development of atherosclerosis.
Studies in mice with targeted gene inactivation of t-PA, u-PA, PAI-1, the urokinase receptor (u-PAR), and plasminogen (Plg) revealed (1) that deficiency of t-PA or u-PA increase the susceptibility to thrombosis associated with inflammation and that combined deficiency of t-PA:u-PA or deficiency of Plg induces severe spontaneous thrombosis; (2) that vascular injury-induced neointima formation is reduced in mice lacking u-PA-mediated plasmin proteolysis, unaltered in t-PA- or u-PAR-deficient mice and accelerated in PAI-1-deficient mice, but that it can be reverted by adenoviral PAI-1 gene transfer; and (3) that atherosclerosis in mice doubly deficient in apolipoprotein E (apoE) and PAI-1 is reduced after 10 weeks of cholesterol-rich diet.
Thus the structural differences between human APOE3 and mouse ApoE proteins are sufficient to cause an increased susceptibility to dietary-induced hypercholesterolemia and atherosclerosis in the 3/3 mice.
A small number of proteins have been shown in vitro to be upregulated by cellular cholesterol loading, including apolipoprotein E (apoE) and the recently cloned HDL-binding protein (HBP), but only apoE has been shown to be upregulated in cholesterol-loaded cells in atherosclerosis.