Hypercholesterolemia increases coronary endothelial dysfunction, lipid content, and accelerated atherosclerosis after heart transplantation.

Hyperlipidemia may increase endothelial damage and promote accelerated atherogenesis in graft coronary vasculopathy. To study the effects of hypercholesterolemia on coronary endothelial dysfunction, intimal hyperplasia, and lipid content, a porcine model of heterotopic heart transplantation, allowing nonacute rejection without immunosuppressive drugs, was used. A high cholesterol diet was fed to donor and recipient swine 1 month before and after transplantation.

Formation of cholesterol monohydrate crystals in macrophage-derived foam cells.

In a previous study using the J774 macrophage foam cells, we quantitated the accumulation of unesterified (free) cholesterol derived from cholesteryl ester hydrolysis in lysosomes, after phagocytic uptake of cholesteryl ester droplets. In the present study, we examined whether the accumulation of free cholesterol in lysosomes leads to the formation of cholesterol monohydrate crystals by analyzing the lipid composition of low density lysosome fractions isolated from cholesteryl ester-loaded macrophages after a 24-h incubation. Phase diagrams of the constituent lipids in the lipid-filled lysosomes predicted the formation of cholesterol monohydrate crystals.

Lysosomal accumulation of unesterified cholesterol in model macrophage foam cells.

Lysosomal accumulation of unesterified (free) cholesterol, following the phagocytic incorporation of cholesteryl oleate lipid droplets, was quantitatively characterized in a murine J774 macrophage foam cell model. The induction of phagocytic incorporation by the macrophages, using an inverted culture technique, allowed the rapid delivery of large amounts of cholesteryl ester droplets to the lysosomes, leading to the subsequent generation of free cholesterol. The lysosomally generated free cholesterol was differentiated from the membrane cholesterol by a double radiolabeling procedure.

Apolipoproteins, membrane cholesterol domains, and the regulation of cholesterol efflux.

Published data related to both cell membrane biology and apolipoprotein structure are reviewed and used to formulate a new model describing the mechanisms of cholesterol efflux from cell plasma membrane to high density lipoprotein (HDL) particles. The central premise of this model is the existence of heterogenous domains of cholesterol within plasma membranes. We propose that cholesterol efflux from cell membranes is influenced by three factors: 1) the distribution of cholesterol between cholesterol-rich and cholesterol-poor membrane domains, 2) the diffusion of cholesterol molecules through the extracellular unstirred water layer, and 3) the transient interaction of segments of the amphipathic helix of the HDL apolipoprotein with cholesterol-poor membrane domains resulting in enhanced cholesterol efflux.

Cellular cholesterol efflux. Role of cell membrane kinetic pools and interaction with apolipoproteins AI, AII, and Cs.

Efflux of [14C]cholesterol from various cells was monitored in the presence of discoidal complexes of egg phosphatidylcholine and purified apolipoproteins, containing either apoAI, AII, or Cs. Particles containing apoAI were more efficient acceptors than those containing apoAII or Cs when the donor cells were J774 macrophages. No differences were observed when the same acceptor preparations were exposed to Fu5AH rat hepatoma or rabbit aortic smooth muscle cells.